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DIGESTION  AND  METABOLISM 


THE  PHYSIOLOGICAL  AND  PATHOLOGICAL 
CHEMISTRY  OE  NUTRITION 


FOE  STUDENTS  AND  PHYSICIANS 


BY 


ALONZO  ENGLEBEET  TAYLOE,  M.D. 

RUSH    PROFESSOR   OF   PHY8IOLOGICAL    CHEMISTRY,    UNIVERSITY   OF   PENNSYLVANIA,    PHILADELPHIA 


LEA    &    FEBIGER 

PHILADELPHIA    AND    NEW    YORK 


% 


Entered  according  toUtfe^cfc  of  £>ytfgres3,:m  £Jie»yeaV:1912,  by 
in  the  office  of  the  Librarian  of  Congress.     All  rights  reserved. 


n( 


i/ 


DEDICATED 
TO 

MADELEINE  PECK  TAYLOR 


v 


PREFACE 


The  author  is  convinced  from  perusal  of  current  medical  writings 
in  this  country  that  there  is  need  among  American  physicians  for  a 
work  presenting  the  subjects  of  Digestion  and  Metabolism  in  a  popular 
manner,  without  technical  details,  and  from  the  standpoint  of  dynamics 
rather  than  from  that  of  analytical  statics  usually  occupied  by  text- 
books of  physiological  chemistry.  He  has  rewritten  in  the  form  of  a 
concise  and  systematic  treatise  the  substance  of  his  lectures  in  this 
field.  No  effort  has  been  made  to  prepare  an  encyclopedic  survey  or 
a  methodic  synopsis  of  the  very  extensive  literature  of  these  subjects, 
but  rather  to  offer  a  practical  interpretation  of  them  in  their  present 
state  of  development. 

The  aim  of  the  book  is  to  describe  the  chemical  changes  in  normal 
and  abnormal  digestion,  and  explain  the  known  metabolic  modifications 
that  food  materials  undergo  within  the  body.  This  understanding 
makes  for  comprehension  of  the  pathology  of  diseases  that  may  be 
termed  metabolic — such  as  gout,  diabetes,  nephritis,  autointoxication 
and  the  results  of  indigestion.  In  a  word,  the  aim  is  to  give  the 
student  and  practitioner  a  working  knowledge  of  just  what  is  known 
to  occur  in  the  chemistry  of  the  normal  body  and  also  of  the  changes 
concerned  in  many  widespread  and  important  diseases.  Variations 
and  findings  in  morbid  states  have  been  everywhere  considered. 

The  student  and  practitioner  of  the  art  and  science  of  medicine 
will  gain  the  most  definite  idea  of  physiological  processes  and  chemical 
functions  if  they  view  them  as  a  moving  picture;  in  other  words,  if 
they  will  consider  them  dynamically  rather  than  statically.  The 
experimental  method  alone  has  enabled  us  to  acquire  the  larger  portion 
of  our  present  knowledge  of  digestion  and  metabolism.  Ability  to 
think  in  the  terms  of  the  experimental  method  is  essential  to  an  under- 
standing of  these  subjects.  The  student  and  physician  need  more 
than  facility  in  method,  invaluable  as  this  is.  They  need  the  dynamic 
concept  of  function  on  which  to  found  a  dynamic  conception  of  disease. 
The  definition  of  experiment  is  fundamental  to  the  concept  of  function, 


vi  PREFACE 

which  in  turn  is  the  foundation  of  the  understanding  of  disease.  The 
following  pages  attempt,  with  the  minimum  of  technical  details,  to 
offer  a  presentation  and  interpretation  of  the  broad  functions  of  diges- 
tion and  metabolism  from  the  standpoint  of  chemical  dynamics. 

The  proper  introduction  of  references  to  literature  is  very  difficult, 
for  one  cannot  emphasize  here  and  reject  there  without  entering  into 
the  details  of  the  several  investigations  in  order  scientifically  to  justify 
acceptance  or  omission  of  reported  data.  The  first  third  of  this  work 
was  written  with  full  references  to  literature.  It  was  then  apparent 
that  the  references  made  up  a  third  of  the  text.  The  direct  references 
occupied  much  space,  and  the  necessary  discussion  of  them  forced  the 
inclusion  of  much  technical  detail.  The  work  was  then  frankly  recast 
into  a  direct  interpretation  of  the  subject  matter,  necessarily  some- 
what dogmatic  and  representing,  in  part,  simply  the  judgment  of  the 
author.  The  method  of  procedure  has  been  to  let  the  facts  point  the 
way  to  theory,  though  in  some  instances  it  has  seemed  necessary  to 
appeal  to  theory  to  aid  in  the  interpretation  of  facts. 

The  newer  nomenclature  of  ferments  has  been  employed.  With- 
out considerations  of  philological  warrant,  an  arbitrary  distinction  has 
been  made  in  the  use  of  terms  derived  from  glycogen  and  glucose. 
Thus  " glycogenesis"  and  "glycolysis"  mean  respectively  the  formation 
of  glycogen  from  glucose,  and  the  cleavage  of  glycogen  into  glucose; 
"glucolysis"  and  "glucosuria"  mean  the  destruction  of  glucose  and 
the  presence  of  glucose  in  the  urine,  respectively,  etc.  In  the  matter 
of  chemical  nomenclature,  an  extreme  position  has  been  avoided. 

A.  E.  T. 

Philadelphia,  1912. 


\ 


CONTENTS 


CHAPTER  I 

The  Composition  of  Foodstuffs .       17 

CHAPTER  II 

The  Theory  of  Ferment  Action ,  .55 

CHAPTER  III 
Digestion 113 

CHAPTER  IV 

The  Carbohydrate  Metabolism 228 

CHAPTER  V 
The  Fat  Metabolism 342 

CHAPTER  VI 
The  Protein  Metabolism 370 

CHAPTER  VII 
The  Metabolism  of  Creatin-Creatinin  and  of  Purins      .....     423 

CHAPTER  VIII 
Autointoxication .     461 

CHAPTER  IX 
Metabolism  Considered  as  a  Whole 468 

CHAPTER  X 
Production  of  Body  Heat  and  Regulation  of  Body  Temperature      .      .     509 


DIGESTION  AND  METABOLISM 


CHAPTER   I 

THE  COMPOSITION  OF  FOODSTUFFS 

The  foodstuffs  are  divided  into  three  natural  groups — carbohydrates, 
fats,  and  proteins.  These  are  all  energy-carrying  materials,  substances 
from  which  tissues  are  formed,  with  which  they  are  maintained,  and 
through  whose  combustion  the  heat  necessary  for  the  life  of  higher 
animals  is  derived.  The  inorganic  salts  are  not  to  be  regarded  as 
foods,  indispensable  as  they  are  to  the  life  of  cells.  They  combine  with 
the  organic  components  of  tissues  and  they  maintain  physico-chemical 
conditions  under  which  living  cells  display  the  chemical  functions  of 
life.  While  they  are  indispensable  to  tissue  structure  and  to  functiona- 
tion,  the  term  food  would  best  be  restricted  to  substances  that  carry 
energy  into  the  organism.  An  elaborate  chemical  description  of  food- 
stuffs does  not  fall  within  the  scope  of  this  treatise,  and  only  such 
description  will  be  given  as  seems  needed  for  the  explicit  purpose  of 
this  work. 

THE   CARBOHYDRATES 

Under  the  term  carbohydrates  (meaning  carbon  combined  with 
hydrogen  and  oxygen  in  the  relations  that  hold  in  water)  we  include 
all  forms  of  sugars,  or  saccharids  as  they  are  now  termed.  The 
saccharids  are  divided  into  four  main  classes:  Monosaccharids, 
di-  and  trisaccharids,  polysaccharids,  and  celluloses.  The  monosac- 
charids, primary  sugars,  are  the  simple  substances  from  which  all 
the  larger  carbohydrates  are  formed.  When  two,  three,  or  even  four" 
molecules  of  primary  sugar  are  combined,  we  speak  of  a  di-,  tri-,  or 
tetrasaccharid.  In  the  polysaccharid,  an  indeterminate  though  large 
number  of  molecules  of  primary  sugar  combine  to  form  a. huge  mole- 
cule. The  celluloses  are  of  still  larger  molecular  dimensions.  The 
monosaccharids  are  of  small  molecular  dimension,  very  soluble,  diffu- 
sible, not  dissociated  in  the  ordinary  sense  of  the  term,  usually  typically 
crystalloidal,  and  their  solutions  present  low  surface  tension  and  high 
osmotic  pressure.  The  disaccharids  are  also  crystalloidal,  very  soluble, 
diffusible,  and  their  solutions  present  low  surface  tension  and  high 
2 


18  ;     :  ::  ■  l^BE  COMBOS!  T^VN  OF  FOODSTUFFS 

osmotic  pressure.  With  the  polysaccharids,  or  starches,  the  properties 
are  very  different.  Starches  are  hydrophilic  colloids;  colloids  that 
with  water  form  emulsions  in  which  the  relations  of  the  colloid  to  the 
water  are  expressed  in  degrees  of  viscosity.  These  colloidal  solutions 
present  high  surface  tension  and  low  osmotic  pressure,  they  diffuse 
little  and  possess  no  tendencies  to  crystallization.  Celluloses  are  sus- 
pension colloids,  they  do  not  form  emulsions  with  water,  there  is  no 
relation  between  the  colloid  and  water,  they  display  little  viscosity  and 
no  diffusibility.  Cellulose  suspended  in  water  is  in  fact  almost  as 
inert  as  talcum. 

Aldoses  and  Ketoses. — The  primary  sugars  that  are  concerned  in  the 
bodies  of  higher  animals  are  aldehyds  or  ketons  of  polyhydric  alcohols; 
the  aldehyd  sugars  are  termed  aldoses,  the  keton  sugars  being  termed 
ketoses.  The  molecule  of  primary  sugar  is  represented  as  having  the 
several  carbon  atoms  in  chains,  i.  e.,  the  alcohols  are  linked  at  the 
carbon  atoms.  Thus  we  speak  of  tetroses,  pentoses,  hexoses,  contain- 
ing respectively  four,  five,  and  six  atoms  of  carbon.  All  primary  sugars 
contain  one  or  two  primary  alcohol  groups  (CH2OH),  and  one  or  more 

secondary  alcohol   groups  (CHOH),  and  the  aldehyd   group  (CHO), 

I'..  • 

or  the  keton  group  (CO).     The  different  primarv  sugars  may  all  be 

I 
synthesized  from  formaldehyd  as  the  starting  point.      Though  it  is 

not  possible  to  regard  these  chemical  operations  as  illustrating  the 

modus  operandi  in  nature,  it  is  still  a  fact  that  the  natural  starting 

point  for  the  synthesis  of  sugars  in  plants  is  formaldehyd.     In  nature, 

however,  we  are  able  to  observe  only  certain  stages.    Thus  we  are  not 

able  to  observe   any  stage   between   the  formaldehyd  and   the  first 

natural  sugar  glycerose  (a  triose);  from  the  triose  to  the  pentose  also 

we  can  observe  no  stage  of  transition.    The  hexose  is  the  commonest 

form  of  primary  sugar  in  nature,  though  pentoses  are  widely  distributed 

in  plants. 

The  simplest  formulation  for  the   reduction  of  carbon   dioxid   to 

formaldehyd  is  as  follows : 

2  C02  +  2  H20  =  2  HCOOH  +  02  Formic  acid 

2HCOOH  =  2HCOH     +  02  Formaldehyd 

1  It  can  be  shown  experimentally  that  chlorophyl  isolated  from  leaves 
of  plants  is  able  in  the  presence  of  sunlight  to  generate  formaldehyd 
from  water  and  carbon  dioxid,  and  the  scheme  corresponds  perfectly 
with  the  respiration  of  plants.  Light  is  essential  to  the  demonstrable 
reaction.  Electro-chemically,  the  reaction  can  be  accomplished  in  the 
absence  of  any  photo-chemical  influence  by  the  presence  of  ozone  and 
hydrogen  peroxid. 

302  =  203 

03  +  H20     =  H202       +  02 

H202  -f  C02  =  H.COH  +  03 


THE  CARBOHYDRATES  19 

Glycollic  aldehyd  also  appears  in  traces  (CHO.CH2OH). 

The  synthesis  of  formaldehyd  in  nature  we  may  thus  define  as  a 
photo-chemical  reaction,  occurring  under  the  influence  of  chlorophyl 
as  an  accelerator,  whereby  carbon  dioxid  is  reduced  to  formaldehyd. 

The  next  step  consists  in  the  condensation  of  formaldehyd  to  a 
sugar.  This  is  supposedly  not  a  biose  but  a  triose,  probably  glycerose. 
Glycerose  has  the  equation: 

CHO 

I 
CHOH 


I 


H2OH 

Isomerism. — We  observe  here  one  of  the  most  fundamental  properties 
of  the  sugars  and  of  many  other  bodies — stereo-isomeric  isomerism. 
It  is  this  condition  within  the  molecule  upon  which  is  founded  the 
power  possessed  by  sugars  of  rotating  the  plane  of  polarized  light. 
This  function  rests  in  the  condition  of  asymmetry  in  the  bindings  of 
the  carbon  atoms.  Carbon  is  in  the  sugars  tetravalent.  \  When  any 
two  (or  more)  of  the  four  bonds  of  a  carbon  atom  are  bound  to  the 
same  element,  group,  or  mass,  the  carbon  atom  is  symmetric;  but  when 
all  four  bonds  are  bound  to  different  elements,  groups,  or  masses,  the 
carbon  atom  is  asymmetric77  All  compounds  containing  asymmetric 
atoms  of  carbon  (unless  this  is  in  some  way  compensated  for)  rotate 
the  plane  of  polarized  light.    Thus  for  glycerose: 


CHO 
HOH 
OH 


h. 

CH2( 


Obviously  the  centre  carbon  is  asymmetric,  and  glycerose  rotates  the 
plane  of  polarized  light.  Since  the  bindings  of  two  of  the  bonds  of 
the  centre  atom  of  carbon  are  reversible,  it  follows  that  there  are  two 
forms  of  glycerose: 

H  H 

C=0  C=0 

H— C— OH  HO— C— H 

H— C— OH  H— C— OH 

A  i 

one  of  which  rotates  the  plane  of  polarized  light  to  the  right,  the 
other  to  the  left.  If  equal  amounts  of  each  form  be  mixed,  these 
rotations  will  be  compensated  and  the  mixture  is  inactive,  or  rather 
balanced.  The  prefixes  1  and  d  were  once  applied  to  the  direction  in 
which  the  plane  of  polarized  light  was  rotated;  now  they  are  applied  to 


20 


THE  COMPOSITION  OF  FOODSTUFFS 


indicate  the  intramolecular  groupings  in  the  sugar  molecule.  Through- 
out this  book,  the  asymmetric  atoms  of  carbon  in  equations  will  be 
printed  in  italics. 

Pentoses. — The  smallest  sugars  concerned  in  the  metabolism  of 
plants  and  animals  in  a  demonstrable  sense  are  pentoses — sugars  with 
five  atoms  of  carbon.  A  pentose  contains  three  asymmetric  atoms  of 
carbon;  and  as  that  number  of  stereoisomeric  configurations  of  the 
molecule  exist  as  are  related  to  the  number  of  asymmetric  atoms  of 
carbon  in  the  proportion  of  2n  where  n  is  the  number  of  asymmetric 
carbon  atoms,  it  is  evident  that  there  must  be  eight  possible  forms  of 
aldo-pentose.  Of  these  eight,  six  are  of  interest  in  biology:  the  two 
forms  of  arabinose,  of  xylose  and  of  ribose. 


d-ribose 

COH 
HCOH 

HCOH 

I 
HCOH 

CH2OH 


l-ribose 

COH 

I 
HOCH 

I 
HOCH 

I 
HOCH 


A 


l-xylose 

COH 

I 
HCOH 

I 
HOCH 

HCOH 


H2OH 


A 


H2OH 


d-xylose 

COH 

I 
HOCH 

I 
HCOH 

I 
HOCH 

I 
CH2OH 


1-lyxose 

COH 
HCOH 
HCOH 
HOCH 

CH2OH 


d-lyxose 

COH 
HOCH 
HOCH 
HCOH 
CH2OH 


l-arabinose 

COH 

I 
HCOH 

I 
HOCH 

I 
HOCH 


A 


H2OH 


d-arabinose 

COH 

I 
HOCH 

I 
HCOH 

HCOH 

I 
CH2OH 


These  pentoses  occur  free  to  but  slight  extent  in  plants,  and  under 
normal  conditions  never  free  in  animals.  They  occur  in  both  plants 
and  animals  in  complex  combinations. 

Aldohexoses. — Of  the  sixteen  possible  aldohexoses,  twelve  of  which 
have  been  found  in  nature  or  synthesized  in  the  laboratory,  but  two  are 
of  importance  here.  They  are  d-glucose  and  d-galactose;  d-levulose, 
a  keton  sugar,  is  the  third  common  hexose. 


COH 

HCOH 

I 
HCOH 

I 
HCOH 

HCOH 


CH: 


OH 


COH 
HOCH 

HOCH 

I 
HOCH 

HOCH 

CH2OH 


COH 

I 
HCOH 

HCOH 

HCOH 

HOCH 


COH 

I 
HCOH 


HO 


Ah 


CH: 


OH 


HOCH 
HOCH 
CH2OH 


COH 
HOCH 
HOCH 
HOCH 
HCOH 

CH2OH 


COH 

HOCH 

I 
HCOH 

I 
HCOH 

HCOH 

CH2OH 


THE  CARBOHYDRATES 


21 


l-gulose 

COH 

HCOH 

I 
HCOH 

HOCH 

I 
HCOH 

CH2OH 

'd-mannose 

COH 

HOCH 

I 
HOCH 

HCOH 

HCOH 

CH2OH 

d-galactose 

COH 

HCOH 

I 
HOCH 

HOCH 

I 
HCOH 


CH< 


OH 


d-gulose 

COH 

I 
HOCH 

HOCH 

HCOH 

HOCH 

CH2OH 

l-mannose 

COH 
HCOH 
HCOH 

HOCH 

I 
HOCH 

CH2OH 

l-galactose 

COH 
HOCH 

HCOH 

I 
HCOH 

HOCH 

CH2OH 


d-glucose 

COH 

HCOH 

HOCH 

HCOH 

HCOH 

CH2OH 

d-idose 

COH 
HCOH 
HOCH 

HCOH 
HOCH 
CH2OH 

d-levulose 

CH2OH 

ho 

HOCH 

I 
HCOH 

HCOH 

CH2OH 


l-glucose 

COH 
HOCH 

HCOH 
HOCH 
HOCH 
CH2OH 

l-idose 

COH 
HOCH 

HCOH 
HOCH 
HCOH 
CH2OH 

I-levulose 

CH2OH 

Ao 

I 

HCOH 
HOCH 
•  HOCH 
CH2OH 


d-levulose  and  1-levulose  are  derivations  of  d-glucose  and  l-glucose, 
being  the  corresponding  keton  sugars.  Each  of  these  contains  a  primary 
alcohol  group  at  the  lower  end  of  the  chain,  and  the  two  levuloses  also 
another  at  the  upper  end,  replacing  the  aldehyd  group  that  is  situated 
at  the  upper  end  of  the  chain  in  the  aldohexose.  The  glucoses  and 
galactoses  have  four  groups  each  of  secondary  alcohol,  these  contain- 
ing the  asymmetric  atoms  of  carbon;  the  levuloses  have  only  three, 
but  contain  the  keton  group.  These  different  hexoses  tend  to  become 
converted  into  each  other  by  intramolecular  re-arrangement,  reactions 
that  can  be  easily  accomplished  in  the  presence  of  dilute  alkali.  In  a 
certain  sense,  the  d-glucose  seems  to  be  the  most  stable  configuration, 
the  one  toward  which  d-galactose  and  d-levulose  tend.  D-glucose 
and  d-galactose  rotate  the  place  of  polarized  light  to  the  right,  respec- 
tively (a)D  =  +  52.5°  and  +  81°.  D-levulose  (named  d-  on  account 
of  its  relationship  to  d-glucose)  rotates  the  plane  of  polarized  light 
to  the  left,  (a)D  =  —  94°.  Very  specific  are  the  relations  of  these 
sugars  to  ferments  and  to  physiological  action,  which  properties  are 
the  expressions  of  intramolecular  configuration. 


22  THE  COMPOSITION  OF  FOODSTUFFS 

Glucosids. — Monosaccharids  combine  with  alcohols,  aldehyds,  and 
aromatic  bodies  to  form  ether-like  combinations  that  are  termed 
glucosids.  The  alcohol  with  which  combination  is  effected  may  be 
another  monosaccharid,  and  thus  the  disaccharids  are  also  to  be 
regarded  as  glucosids.  Whether  the  pentoses  form  disaccharids  is 
not  clear,  and  in  any  event  it  is  of  no  importance  to  us  here.  The 
hexoses  form  stable  disaccharids,  of  great  importance  as  the  common 
sugars,  namely,  cane  sugar,  malt  sugar,  and  milk  sugar.  Maltose  is 
a  combination  of  two  molecules  of  d-glucose,  and  is  thus  the  glucosid 
of  d-glucose.  Cane  sugar,  or  sacchrose,  is  a  combination  of  d-glucose 
and  d-levulose,  and  is  thus  the  fructosid  of  d-glucose.  Milk  sugar  is 
a  combination  of  d-galactose  with  d-glucose,  and  is  thus  the  galactosid 
of  d-glucose.  All  such  combinations  of  hexoses  to  form  disaccharids 
follow  the  equation: 

Hexose   +  hexose     =  disaccharid  +  water 
C6H12O6  +  CeH^Oe  =  C12H22O11      +  H2O 

Conversely,  when  a  disaccharid  is  split,  the  reaction  is  one  of  hydro- 
lysis. The  rotary  powers  of  the  disaccharids  cannot  be  calculated 
from  those  of  their  components.  Thus  maltose  rotates  the  plane  of 
polarized  light  to  the  right  (a)D  =  +  138°,  saccharose  (a)D  =  + 
66.5°,  and  lactose  (a)D  =  +  52.5°.  The  configuration  of  the  disac- 
charids is  not  understood.  Some  of  the  common  reactions  are  also 
not  clear.  Thus  maltose  reduces  copper  in  both  alkaline  and  acid 
reaction,  lactose  only  in  alkaline  reaction,  while  saccharose  cannot 
effect  reduction  at  either  reaction.  The  importance  of  disaccharid 
to  the  human  diet  is  evident  when  we  recall  that  the  cane-sugar  produc- 
tion of  the  world  is  something  like  15,000,000  tons  per  annum. 

Polysaccharids. — The  pentoses  as  well  as  the  hexoses  form  poly- 
saccharids.  The  polysaccharids  of  pentose  are  termed  pentosans, 
widely  distributed  in  plants  and  of  great  importance  in  the  diet  of 
herbivora.  The  polysaccharids  of  glucose  are  starches,  glycogens, 
dextrins,  lichinins,  some  native  gums,  and  cellulose.  The  polysac- 
charids of  levulose  are  termed  fructans,  and  of  these  inulin  is  an  illus- 
tration. The  polysaccharids  of  d-galactose  are  termed  galactans, 
and  many  native  gums  belong  to  this  group.  The  number  of  mole- 
cules of  primary  sugar  in  these  polysaccharids  is  not  known.  The 
method  of  combination  is  identical  with  that  of  the  combination  of 
the  primary  sugars  to  form  disaccharids — water  is  extruded.  Thus 
we  usually  .express  the  formation  of  a  starch  as  follows : 

n  glucose    +  n  glucose   =  n  starch  +  n  water 

n  C6H1206  +  n  C6H1206  =  n  (C6H10O6)n  +  n  H20 

The  converse  of  this  reaction,  the  cleavage  of  a  starch  into  its  com- 
ponent primary  sugars,  is  obviously  a  reaction  of  hydrolysis.  The  pen- 
tosans, fructans,  gums,  and  cellulose,  while  of  importance  to  the  diet  of 


THE  FATS  2% 

herbivora,  are  of  little  importance  to  man,  and  the  same  may  be  said 
of  the  lichen  starches.  It  is  the  common  starches  and  their  derivatives 
that  constitute  the  fuel  of  the  race.  The  starch  production  of  the 
world  is  something  like  150,000,000  tons  per  annum,  or  about  ten 
times  the  production  of  sugar. 

Caloric  Values. — The  caloric  values  of  the  carbohydrates  are:  Starch, 
4.1  Cal.;  disaccharids,  3.95  Cal.,  and  hexoses,  3.75  Cal.  per  gram.  They 
have  the  same  heat  values  in  the  animal  body  as  in  the  calorimeter, 
i.  e.y  the  body  burns  them  completely. 


THE    FATS 

The  fats  are  esters,  combinations  of  fatty  acids  with  an  alcohol. 
The  common  fats  of  plants  and  animals  are  combinations  of  palmitic, 
stearic,  and  oleic  acids  with  the  triatomic  alcohol,  glycerol  (glycerin). 
Palmitic  and  stearic  acids  are  members  of  the  series  CnH2Q02,  and 
have  respectively  the  formulae  C15H31COOH  and  C17H35COOH.  A  few 
of  the  lower  members  of  this  series  occur  in  milk  and  in  some  plants; 
such  are  butyric  acid  (C3H7COOH);  caproic  acid  (C5HnCOOH); 
caprylic  acid  (C7H15COOH),  and  capric  acid  (C9H19COOH).  They 
occur,  however,  only  in  traces,  and  cannot  be  said  to  possess  any 
importance  as  foodstuffs.  Oleic  acid  is  a  member  of  the  unsaturated 
series  CnH2n-2  02,  and  has  the  equation: 
CgHi6H\  /H 

W  X(CH2)7  COOH 

The  fats  of  fishes  and  of  marine  mammals  contain  other  fatty  acids 
and  also  other  alcohols  than  glycerol.  The  fats  are  formed  largely 
if  not  entirely  from  sugar  in  the  metabolism  of  plants.  While  it  can- 
not be  denied  that  plants  may  build  up  the  higher  fatty  acids  directly 
from  the  lowest  member  of  the  group,  formic  acid,  the  evidence  is 
strongly  in  favor  of  their  formation  from  sugar.  In  the  germination 
of  seeds,  the  fat  contained  in  them  is  reconverted  into  glucose,  and 
for  plants  the  fat  evidently  represents  a  storage  form  of  sugar,  analogous 
to  starch,  though  quantitatively  of  less  importance.  The  fats  of  most 
plants  consist  largely  of  the  esters  of  oleic  and  palmitic  acids;  stearic 
acid  on  the  other  hand  is  prominent  in  the  fats  of  many  animals. 

In  the  combination  of  fatty  acid  with  glycerol,  each  of  the  three 
hydroxyl  groups  of  the  alcohol  binds  a  molecule  of  fatty  acid  by  linkage 
with  the  carboxyl  group,  water  being  extruded. 

Tripalmitin  Water 

CH2.O.OC.Ci5H3i  H20 
CH  .O.OC.C15H31  +  H20 
CH2.O.OC.Ci5H3i       H20 


Glycerol 

Palmitic  acid 

CH20 

H 

HO 

OC .  C15H31 

CHO 

H 

+     HO 

OC .  C15H31 

CH20 

H 

HO 

OC .  C15H31 

24  THE  COMPOSITION  OF  FOODSTUFFS 

When  a  fat  is  hydrolyzed,  the  reaction  is  just  the  reverse,  water  is 
added,  and  the  fat  split  into  the  component  fatty  acids  and  glycerol. 
If  the  hydrolytic  cleavage  be  accomplished  through  the  agency  of 
heat  alone,  as  with  the  use  of  steam,  or  aided  by  the  catalytic  action 
of  acids,  the  products  are  free;  if  the  cleavage  be  accomplished  through 
the  action  of  alkali,  soaps  are  formed.  The  soaps  of  ammonia,  sodium, 
and  potassium  are  soluble  in  water,  those  of  calcium  and  magnesium 
are  relatively  insoluble.  The  soaps  of  triolein  are  more  soluble  than 
the  soaps  of  tristearin. 

Melting  Point  of  Glycerids. — The  melting  points  of  the  three  glycerids 
are  as  follows:  Triolein,  4°;  tripalmitin,  62°;  and  tristearin,  72°. 
These  are  physical  melting  points.  When  the  three  glycerids  are  com- 
bined in  a  natural  fat,  the  melting  point  of  the  mixture  depends  largely 
upon  the  relative  amounts  of  triolein  and  tristearin.  The  greater 
the  fraction  of  tristearin,  the  higher  the  melting  point;  the  greater 
the  fraction  of  triolein,  the  lower  the  melting  point.  The  melting 
point  of  a  natural  fat  is  not  a  physical  melting  point  at  all,  but  rather 
something  akin  to  a  saturation  point.  The  triolein  acts  as  solvent  for 
the  other  two  glycerids,  and  the  temperature  at  which  the  fat  becomes 
fluid  is  the  point  at  which  the  triolein  present  is  able  to  hold  the  other 
two  glycerids  in  solution.  The  melting  points  of  the  several  natural 
fats  are  as  follows:  Horse  fat,  60°  to  65°;  mutton  fat,  50°  to  55°;  beef 
fat,  45°  to  50°;  lard,  35°  to  40°;  human  fat,  35°  to  40°,  and  dog  fat, 
20°  to  30°.  The  melting  point  of  the  fat  of  the  dog  varies  widely  with 
the  diet,  as  is  the  case  with  the  fat  of  man;  the  fats  of  the  other  animals 
vary  less.  As  will  be  pointed  out  later,  the  melting  points  of  fats  have 
a  bearing  upon  their  digestibility;  other  things  being  equal,  the  lower 
the  melting  point  of  a  fat  and  the  more  soluble  a  fat,  the  greater  the 
digestibility. 

Caloric  Values. — Fat  is  the  most  concentrated  form  of  energy  in  a 
foodstuff.  One  gram  of  a  fat  of  mean  molecular  weight  of  the  three 
glycerids  will  yield  9.4  Calories  of  heat.  When  the  degree  of  resorption 
of  fat  is  normal  this  amounts  to  about  9  Calories  per  gram  of  fat  ingested, 
and  this  is  the  figure  usually  used  in  diet  calculations.  This  is  obviously 
over  twice  the  heat  value  of  either  glucose  or  protein.  Since  man  is  an 
animal  endowed  with  locomotion,  it  is  a  fact  of  great  practical  impor- 
tance that  fuel  is  stored  in  the  form  of  fat  instead  of  in  the  form  of 
starch. 

THE   PROTEINS 

The  composition  and  constitution  of  the  proteins  are  of  great  com- 
plexity. The  physical  and  chemical  attributes  of  the  different  members 
of  this  large  class  are  very  manifold  and  are  not  to  be  grouped  under 
rigid  classification.  Proteins  may  be  defined  briefly  as  condensation 
compounds  of  amino-acids.  The  physical  attributes  of  these  com- 
pounds have  less  bearing,  at  present  at  least,  upon  the  processes  of 


THE  PROTEINS  25 

digestion  and  metabolism,  than  the  chemical  properties.  To  the- former, 
therefore,  we  will  devote  less  detail  in  description  than  to  the  latter. 
The  details  of  the  qualitative  organic  chemistry  of  protein  are  of  funda- 
mental importance  to  the  interpretation  of  the  metabolism  of  protein 
in  the  body. 

Molecular  Weight. — The  molecular  weights  of  proteins  are  large,  but 
not  accurately  determinable.  Various  approximations  for  different 
proteins  run  from  3000  to  20,000.  Despite  the  fact  that  iron  is  com- 
bined in  hemoglobin  in  definite  proportions,  despite  the  fact  that 
proteins  combine  with  many  metals,  despite  estimations  of  the  sulphur 
in  native  proteins,  it  has  not  been  possible  to  fix  the  molecular  weight. 
There  is  good  evidence  that  proteins  can  exist  in  two  states — as  single 
molecules  and  as  aggregates  of  molecules.  To  this  fact  are  due  many 
of  the  anomalous  behaviors  of  proteins  under  different  conditions  of 
solution  or  suspension. 

Colloidality. — The  proteins  are  in  general  termed  colloids.  But 
this  designation  must  be  circumscribed.  The  colloidality  of  some 
proteins  is  very  slight,  of  others  marked.  There  are  four  stages  to  be 
outlined,  the  first  of  which  approaches  the  true  solution,  the  last  of 
which  borders  on  the  mechanical  suspension.  Some  proteins  are  quite 
soluble.  Protamin  is  one  of  these.  A  solution  of  protamin  sulphate 
is  as  truly  a  solution  as  is  a  syrup  of  cane  sugar.  All  proteins  in  water 
may  be  regarded  as  having  a  fraction  in  true  solution,  though  in  the 
case  of  most  proteins  this  fraction  is  small.  The  second  stage  is  that 
of  the  hydrophilic  colloid,  and  in  this  stage  most  of  the  proteins  are 
found.  In  the  hydrophilic  colloids  there  is  a  variable  relation  between 
the  colloid  (solute)  and  the  water  (solvent),  and  this  relation  is  expressed 
in  the  viscosity  of  the  solution.  The  third  stage  is  that  of  the  aggregate 
or  micelle.  The  molecules  of  protein  in  water  unite  to  form  aggregates 
that  are  optically  visible  in  reflected  light.  There  is  for  each  protein 
a  relation  between  stages  two  and  three,  reversible,  that  can  be. altered 
by  dilution  or  concentration;  for  some  proteins  the  conglomeration 
is  favored  by  dilution,  in  others  by  concentration.  The  fourth  stage  is 
that  of  the  suspension  colloid,  and  many  proteins  tend  to  this  state. 
Finally,  some  proteins  of  the  connective-tissue  groups  are  as  inert  in 
water  as  talcum.  It  is  clear,  therefore,  that  in  the  domain  of  proteins 
we  find  substances  that  range  from  true  solubility  to  typical  extreme 
colloidality — just  as  in  the  carbohydrates  we  have  substances  ranging 
from  the  true  solubility  of  the  di-,  tri-,  and  tetrasaccharids,  through 
the  dextrins  to  starch  and  finally  to  cellulose.  There  has  been  a 
tendency  to  exaggerate  the  colloidality  of  proteins  and  to  minimize 
their  solubility.    Most  proteins  in  water  are  hydrosols,  few  are  hydrogels. 

The  Tyndall  test  is  of  especial  importance  for  the  study  of  proteins 
in  water.  The  dancing  of  dust  particles  in  the  air  when  a  ray  of  light 
comes  through  a  slit  into  a  darkened  room,  is  a  typical  instance  of  the 
Tyndall  test.  All  proteins  give  this  test,  though  in  some  it  is  slight. 
A  colloidal  solution  appears  white  or  opalescent  in  reflected  light,  for 


26  THE  COMPOSITION  OF  FOODSTUFFS 

the  reason  that  the  particles  reflect  the  light,  which  is  in  part  polarized. 
It  must  be  recalled  that  crystalloids  of  large  molecular  weight  give 
the  Tyndall  test.  A  solution  of  protamin  sulphate  yields  the  test 
to  but  slight  degree,  no  more  than  a  solution  of  raffinose.  From  this 
point  of  view  we  may  divide  proteins  again  into  four  classes:  In  the 
first,  the  particles  are  visible  to  the  naked  eye  and  tend  to  settle  out. 
In  the  second,  the  particles  are  visible  on  ultramicroscopic  vision 
under  all  conditions  of  concentration  and  the  particles  so  visible  are 
termed  submicrons.  By  special  treatment,  such  as  dilution,  it  can  be 
shown  that  a  third  class  exists,  in  which  the  particles  are  still  smaller. 
These  are  termed  amicrons,  and  these  may  be  made  to  conglomerate 
to  submicrons.  Lastly,  under  certain  conditions,  particles  may  be 
encountered,  whose  movements  indicate  on  calculation  that  they  possess 
the  dimensions  of  molecules.  It  is  clear,  therefore,  that  the  results  of 
the  Tyndall  test  and  of  ultramicroscopic  study  lead  to  the  same  view, 
that  proteins  exist  all  the  way  in  the  scale  from  the  large  molecular 
crystalloid  to  the  typical  colloid. 

Filtration  and  Diffusion. — The  results  of  investigations  on  filtration 
and  diffusion  indicate  that  these  are  in  part  arbitrary  processes,  depend- 
ent upon  the  constitution  of  the  filter  and  diffusion  membranes;  and 
in  a  classification  of  the  behavior  of  proteins  on  filtration  and  diffusion, 
account  must  be  taken  of  these  facts.  As  a  rule,  proteins  do  not  diffuse 
through  ordinary  membrane,  though  protamin  sulphate  diffuses  with 
measurable  velocity.  But  it  is  possible  to  so  alter  the  diffusion  mem- 
brane as  to  permit  of  the  diffusion  of  many  proteins.  And,  on  the 
other  hand,  it  is  possible  to  so  condense  the  fabric  of  filters  as  to  retain 
even  the  finest  colloidal  particles.  It  is  also  possible  to  retain  upon 
such  filters  large  molecular  crystalloids.  And  it  is  possible  to  so  modify 
diffusion  membranes  as  to  make  the  diffusion  of  typical  crystalloids 
slow  and  difficult.  From  the  point  of  view  of  the  filter,  it  seems  to  be 
simply  a  question  of  the  size  of  the  particles  or  molecules.  With  the 
diffusion  membrane,  however,  there  seems  to  be  some  relation  of 
the  composition  of  the  membrane  to  the  substance  to  be  diffused;  and 
for  some  apparently  non-diffusible  substances,  the  cause  of  their 
non-diffusion  is  precipitation  in  the  interstices  of  the  membrane.  The 
cellular  membranes  are  comparable  membranes.  These  cell  membranes 
are  all  protein-lipoid  phases,  and  theoretically  could  not  permit  directly 
the  passage  of  any  substance  not  lipo-soluble.  But  amino-acids  and 
sugar  do  pass  into  the  cell  walls;  indeed,  proteins  pass  in,  and,  of  course, 
the  lipo-soluble  fats.  To  pass  through  this  cell  membrane,  the  sub- 
stances must  either  be  made  lipo-soluble  by  complex  chemical  combina- 
tion, or  the  membrane  must  be  made  permeable  to  their  diffusion  through 
adsorption  of  them  by  lipoids.  Experimentally  we  have  analogies 
for  both  processes. 

It  was  once  categorically  stated  that  proteins  could  not  present 
osmotic  pressure  in  their  solutions.  This  is  not  true.  When  the  measure- 
ments are  made  with  delicate  and  properly  adjusted  osmometers,  it 


THE  PROTEINS  27 

can  be  shown  that  pure  proteins  in  solution  exert  a  small  but  demon- 
strable osmotic  pressure.  Since  the  molecular  weights  of  the  proteins 
are  known  to  be  large  and  since  the  osmotic  tension  of  solutions  is 
inversely  to  the  molecular  dimensions  of  the  solute,  but  small  osmotic 
pressure  would  be  expected  in  protein  solutions.  These  run,  as 
measured,  from  3  to  30  mm.  of  Hg.  In  one  sense  it  is  possible  to  regard 
this  osmotic  pressure  as  evidence  that  a  certain  small  fraction  of  the 
protein  exists  in  water  in  true  solution. 

Crystallization. — Despite  their  colloidal  character,  many  proteins 
display  striking  tendencies  to  crystallization.  This  is  not  only  true 
for  the  hemoglobins  (in  which  the  crystallographic  properties  seem  to 
vary  with  the  biological  stamp),  but  also  for  many  of  the  ordinary 
forms  of  protein.  Special  conditions  for  crystallization  must  be  attained, 
though  these  are  often  no  more  complex  or  difficult  than  are  necessary 
in  the  case  of  some  typical  crystalloids. 

Tension. — The  more  colloidal  a  solution  of  a  protein,  other  things 
being  equal,  the  more  marked  is  its  surface  energy,  or  tension,  com- 
pared with  its  volume  energy.  In  such  a  solution,  the  particles  of  the 
colloid  tend  to  surround  themselves  with  a  film  of  saturated  solution  of 
whatever  may  be  present  in  the  system.  The  relation  works  both  ways 
of  course,  the  protein  may  be  either  axis  or  periphery.  It  is  possible 
to  precipitate  proteins  from  a  solution  and  carry  with  them  other 
bodies  therein  present;  or  it  may  be  possible  to  precipitate  a  third 
substance  and  carry  down  with  it  the  protein.  Gases  as  well  as  salts, 
crystalloids  and  colloids  may  be  held  by  adsorption,  and  future  investi- 
gations may  indicate  that  adsorptions  play  prominent  roles  in  animal 
functions. 

Amphoterism. — As  will  be  later  described  in  detail,  proteins  contain 
both  NH2  and  COOH  groups,  and  are,  therefore,  amphoteric,  though 
with  a  greater  basic  or  acid  capacity  in  each  case.  Under  these  cir- 
cumstances, it  becomes  clear  why  proteins  combine  as  acids  or  as 
bases  with  other  acids  and  bases.  These  combinations  are  usually 
very  unstable,  easily  dissociated,  and  tend  in  particular  to  exhibit 
hydrolytic  dissociation.  It  is  when  combined  with  acids  or  alkalies 
that  the  phenomenon  of  cataphoresis  is  displayed.  When  placed  in 
the  field  of  a  galvanic  current,  the  protein  combined  with  acid  migrates 
to  the  cathode,  while  protein  combined  with  alkali  wanders  to  the 
anode.  If  the  acids  or  alkali  be  removed  by  dialysis  or  other  means, 
these  migrations  do  not  occur.  Obviously,  the  particles  of  pure  protein 
carry  no  charge,  it  is  only  the  acid  or  alkali  that  endows  them  with 
electrical  charges. 

Nearly  all  proteins  rotate  the  plane  of  polarized  light.  This  is  due 
to  the  presence  of  asymmetric  atoms  of  carbon  in  the  several  amino- 
acids  of  which  they  are  composed. 

Gelification. — Certain  proteins  when  brought  into  solution  in  hot 
water,  on  cooling  pass  into  the  state  of  gel.  Certain  carbohydrates 
possess  the  same  property.     This  gelification  is  a  reversible  process; 


28  THE  COMPOSITION  OF  FOODSTUFFS 

if  the  gel  be  warmed  it  becomes  fluid,  to  solidify  again  on  cooling. 
Heating,  however,  tends  to  destroy  this  property;  for  example, 
each  hour's  heating  lowers  the  jelling  point  of  gelatin  1°.  Some 
gels  melt  at  the  same  temperature  at  which  solidification  occurred; 
gelatin  does  so.  Agar-agar,  on  the  other  hand,  does  not  solidify  on 
cooling  until  about  38°,  but  after  it  has  set  must  be  warmed  to  nearly 
100°  before  it  will  become  fluid.  The  metallic  hydrogels  do  not  redis- 
solve  in  water.  The  formation  of  a  gel  is  considered  to  lie  in  a  segrega- 
tion, whereby  two  phases  are  formed,  one  rich  in  protein  and  poor  in 
water,  the  other  rich  in  water  and  poor  in  protein.  The  two  phases 
can  be  distinguished  with  the  microscope,  and  this  demonstration  is 
very  suggestive  for  the  student  of  physiological  structure. 

Coagulation. — Resembling  gelification  in  many  ways  is  the  phenome- 
non of  coagulation  displayed  by  some  proteins.  We  speak  here  of 
ferment  coagulation — the  clotting  of  milk,  of  blood,  and  of  muscle 
plasma — not  heat  coagulation.  The  investigations  to  date  seem  to 
indicate  that  this  process  is  due  to  the  chemical  transformation  of 
the  protein  concerned  into  a  para-stage,  in  which  the  protein  com- 
bined with  calcium,  or  other  cation,  is  segregated  into  an  insoluble 
phase.    The  process  is  irreversible. 

Precipitation. — Colloids  are  often  precipitable  from  their  solutions 
in  water  by  the  addition  of  electrolytes,  metallic  salts.  The  amount  of 
salt  necessary  to  effect  precipitation  varies  with  the  salt  and  with  the 
protein.  The  proteins  that  wander  to  the  anode  are  precipitated  by 
the  cations  of  the  electrolyte;  the  proteins  that  migrate  to  the  cathode 
are  precipitated  by  the  anions.  The  valency  of  the  ions  affects  the 
flocking  power;  the  trivalent  ions  are  the  most  active,  the  bivalent 
next,  the  monovalent  least.  Proteins  display  often  marked  resistance 
or  irregularities  to  these  precipitations;  obviously,  the  preexistent 
salts  would  be  expected  to  modify  the  results.  And  often  it  seems 
quite  impossible  to  induce  flocking  in  protein  solutions.  With  the 
hydrophilic  colloids,  such  as  proteins,  these  flockings  are  reversible. 
The  current  theory  of  these  precipitations  is  that  it  is  an  electrical 
neutralization  process,  and  when  the  charge  of  the  protein  is  just 
neutralized  by  the  charge  of  the  ions,  precipitation  occurs  from  the 
iso-electric  medium. 

Colloids  sometimes  precipitate  each  other,  a  behavior  not  commonly 
seen  among  the  proteins.  It  is  difficult  in  the  instances  where  it  does 
occur  (as  with  protamin  and  albuminous  solutions)  to  know  whether 
we  deal  with  a  chemical  combination  or  a  flocking.  The  explanation 
for  such  precipitation  of  colloids  is  that  colloids  of  opposite  electrical 
charges  precipitate  each  other.  It  is,  however,  not  clear  how  adsorp- 
tion can  be  ruled  out.  Proteins  and  other  hydrophilic  colloids  have 
often  the  property  of  preventing  the  precipitation  of  suspension  colloids 
by  electrolytes.  More  than  this,  they  prevent  the  physical  denatura- 
tion  of  the  suspension  colloids.  If  a  suspension  colloid  in  water  be 
evaporated  to  dryness,  no  colloidal  solution  will  be  formed  on  taking 


THE  PROTEINS  29 

up  the  residue  in  water;  but  if  the  evaporation  occur  in  the  presence 
of  a  protein,  a  colloidal  solution  will  reform  on  the  addition  of  water. 
In  like  manner  the  presence  of  protein  makes  the  filtration  of  a  sus- 
pension colloid  much  easier.  This  protection  of  colloids  by  each  other  is 
probably  a  phenomenon  of  adsorption,  the  protecting  colloid  spreading 
like  a  thin  film  over  the  protected  colloid,  and  modifying  its  physical 
and  chemical  properties.  The  use  of  colloidal  states  of  iron  and  alumi- 
num for  the  flocking  of  sewerage  is  an  illustration  of  the  practical 
application  of  this  phenomenon. 

Denaturation. — When  solutions  of  proteins  are  carefully  evaporated 
to  dryness  at  low  temperatures,  well  below  the  coagulation  point,  they 
form  hard  masses.  These  are  usually  soluble  in  water.  But  in  some 
instances  the  process  is  not  reversible  and  the  protein  refuses  to  again 
pass  into  colloidal  solution.  In  all  cases,  as  time  passes,  the  resolubility 
becomes  more  and  more  difficult,  to  be  finally  lost.  When  proteins 
are  precipitated  by  salting  out,  the  precipitated  and  washed  proteins 
are  usually  resoluble  under  appropriate  conditions.  But  this  is  not 
always  so.  Some  proteins  are  resoluble  after  precipitation  with  alcohol 
and  tannic  acid;  others  are  not.  In  other  words,  in  some  cases  precipita- 
tion means  denaturation,  in  other  cases  not.  The  combinations  with 
the  heavy  metals  are  very  prone  to  cause  denaturation.  With  some 
delicate  proteins  prolonged  shaking  produced  denaturation;  the  proteins 
are  conglomerated  as  definitely  as  churning  conglomerates  the  fat  of 
milk,  and  cannot  be  gotten  back  into  solution. 

A  particular  form  of  denaturation  of  proteins  is  coagulation  by  heat. 
This  process  is  favored  by  salts  and  hastened  also  by  acids  and  alkalies, 
although  the  denaturated  proteins  combine  with  the  acid  and  alkali 
to  form  soluble  compounds.  These  denaturations  are  irreversible. 
They  carry  with  them  also  the  loss  of  the  specific  biological  properties 
of  protein.  We  must,  therefore,  regard  them  as  involving  intra- 
molecular transformations. 

The  physical  and  physico-chemical  states  of  the  colloids  (the  proteins, 
lipoids,  and  animal  starches)  are  unquestionably  of  enormous  impor- 
tance in  modifying  and  indeed  in  determining  chemical  reactions  occur- 
ring in  association  with  them,  both  in  the  quantitative  and  qualitative 
senses.  Protoplasm  may  be  defined  as  a  system  of  heterogeneous 
phases,  the  water  of  solution  forming  multiphase  systems  with  the 
inorganic  salts,  protein,  and  lipoids.  In  the  fluid  phases,  the  water  is 
solvent  and  the  ion-protein-lipoid  solute;  in  the  solid  phase  the  protein 
or  lipoid  is  solvent,  the  water  and  salts  solute.  The  possibilities  in 
such  a  multiphase  system  are  enormous,  both  for  chemical  combina- 
tion and  physical  adsorption.  Concretely,  we  are  not  yet  able  to  take 
account  of  these  factors  when  dealing  with  the  metabolism  of  a  higher 
organism.  Nevertheless,  we  must  always  make  allowance  for  this 
factor,  and  never  forget  that  the  chemical  reactions  in  the  living  body 
occur  not  in  a  homogeneous  medium  but  in  a  two-phase  system. 

Origin  of  Proteins. — The  origin  of  protein  in  the  plant  world,  from 
which  exclusively  it  is  derived  by  higher  animals,  is  well  understood. 


30  THE  COMPOSITION  OF  FOODSTUFFS 

Soils  contain  salts  of  nitric  acid  that  has  been  derived  from  two  sources; 
from  ammonia  originating  in  the  decomposition  of  plant  and  animal 
tissues;  and  from  the  inert  nitrogen  of  the  atmosphere.  The'  conver- 
sion of  the  inert  nitrogen  of  the  air  into  oxid  is  accomplished  by 
bacteria,  certain  classes  of  which  exhibit  this  faculty  to  such  an  extent 
as  to  make  it  their  chief  work;  these  are  termed  nitrifying  bacteria, 
and  with  these  are  inoculated  soils  in  which  are  growing  higher  plants 
upon  whose  roots  they  thrive  well.  There  are  on  the  contrary  bacteria 
that  denitrify,  they  set  free  gaseous  nitrogen  from  nitrates ;  such  bacteria 
are  especially  active  in  waters,  both  inland  and  oceanic,  where  the 
sewage  of  the  world  is  ultimately  disposed  of.  The  oxidation  of 
inert  nitrogen  to  oxid  of  nitrogen  can  also  be  accomplished  by  electro- 
chemical agencies.  Thus  nitric  acid  is  formed  in  traces  in  thunder, 
and  is  being  prepared  commercially  in  large  amounts  by  means  of 
the  electrical  spark,  the  action  of  which  is  usually  interpreted  to  be 
thermo-chemical,  it  being  known  that  at  high  temperature  nitrogen 
and  oxygen  unite.  The  oxid  of  nitrogen  formed  in  the  soil  by  bacteria 
is  reduced  to  NH2  group  in  some  manner  as  yet  unclear,  and  these 
NH2  groups  added  to  the  fatty  acids,  whose  origination  has  already 
been  described,  form  amino-acids. 

On  paper  we  might  assume  that  the  nitrate  is  reduced  to  the  nitrite, 
this  then  passes  into  NH  =  O,  then  combining  with  water  to  form  hy- 
droxylamin,  NH2  =  OH,  which  finally  would  combine  with  formaldehyd 
to  form  formamid  COH.NH2.  There  is  no  experimental  evidence 
of  this  scheme.  These  syntheses  are  specific,  since  all  amino-acids, 
except  that  of  acetic  acid  (glycocoll),  contain  an  asymmetric  atom  of 
carbon.  With  these  amino-acids,  plants  form  their  many  types  and 
kinds  of  protein;  and  this  plant  protein  is  directly  or  indirectly  the 
source  of  all  protein  in  higher  animals. 

The  Chemistry  of  the  Proteins. — When  proteins  are  completely  hydro- 
lyzed,  the  products  consist  of  amino-acids.  These  vary  in  number 
in  the  different  proteins,  and  the  amounts  of  the  several  amino-acids 
also  vary  in  the  different  proteins.  Some  proteins  do  not  contain  all 
the  amino-acids  that  are  to  be  found  in  certain  members  of  the  class; 
some  typical  proteins  indeed  contain  but  a  few  while  others  contain 
a  great  many  amino-acids.  It  will  be  best  to  describe  first  the  different 
amino-acids  that  are  to  be  found  in  the  products  of  the  hydrolysis 
of  proteins,  after  which  the  linkage  of  these  bodies  to  form  proteins 
will  be  described.  Fundamental  to  our  interpretation  of  the  proteins 
as  condensations  of  amino-acids  is  the  fact  that  these  exist  preformed 
in  the  proteins.  No  matter  in  what  manner  and  with  what  reagents 
(different  acids  in  different  concentrations,  different  alkalies  in  different 
concentrations,  ferments,  steam),  the  hydrolytic  cleavages  are  accom- 
plished, the  end  result  in  the  yield  of  amino-acids  is  the  same.  In 
other  words,  the  hydrolysis  does  not  form  amino-acids,  it  does  not 
alter  them,  it  does  not  convert  one  into  another;  it  simply  sets  them 
free,  their  isolation  thereafter  depending  upon  particular  chemical 
methods.     In  this  point  the  reaction  of  the  hydrolysis  of  proteins  is 


THE  PROTEINS  31 

like  the  cleavage  of  the  fats  and  starches.  The  products  are  hexoses 
in  the  case  of  starches,  fatty  acids  and  glycerol  in  the  case  of  the  fats. 
The  reactions  of  hydrolysis  do  not  add  to,  substract  from,  or  in  any 
way  alter  the  component  bodies  that  existed  preformed  in  the  original 
substrates.  The  more  the  technique  of  the  hydrolysis  of  the  proteins 
is  perfected,  the  more  certain  has  it  become  that  the  component  amino- 
acids  exist  preformed  in  the  molecule  of  protein.  The  theoretical 
importance  of  this  conception  lies  in  the  fact  that  we  regard  these 
amino-acids  as  the  building  stones  of  proteins,  it  is  these  that  each 
organism  puts  together  in  accordance  with  the  peculiar  modus  operandi 
of  its  species,  forming  therefrom  protein  structures  of  which  the  archi- 
tecture is  peculiar  to  the  species.  The  amino-acids  are  not  peculiar  to 
the  species,  they  exist  preformed  in  all  proteins,  and  are  the  common 
building  materials  of  all  plants  and  animals,  just  as  brick,  stone,  timbers, 
boards,  and  plaster  are  the  common  building  materials  of  all  races. 
Just  as  the  houses  of  different  peoples  vary  greatly  in  size,  in  architec- 
tural design  and  conformation,  so  the  proteins  of  different  animals 
vary  in  construction. 

The  several  amino-acids  derived  from  proteins  are  all  alpha  amino- 
acids,  i.  e.,  the  NH2  group  is  linked  to  the  alpha  carbon;  in  the  case 
of  the  diamino-acids,  there  is  no  rule  for  the  location  of  the  second 
NH2  group.  (It  will  be  recalled  that  the  carbons  in  the  fatty  acids  are 
named  in  succession  above  the  carboxyl,  alpha,  beta,  gamma,  delta, 
epsilon.)  The  presence  of  the  NH2  and  the  COOH  groups  gives  to 
these  bodies  basic  and  acid  (amphoteric)  characters;  they  combine 
with  acids  and  bases  to  form  salts,  which  being  subject  to  a  marked 
hydrolytic  dissociation  are  in  watery  solution  acid  or  alkaline  in  reac- 
tion. They  combine  with  alcohols  to  form  esters,  which  are  bases; 
they  combine  with  aldehyds  to  form  methyl  combinations  that  are 
acids.  These  may  be  illustrated  for  the  reaction  of  glycocoll  with 
ethyl  alcohol  and  formaldehyd  respectively: 

CH2NH2  CH2NH2 

|  +  C2H5OH  =    | 

COOH  CO.O.C2H5 

CH2NH2  CH2NCH2 

+  HCOH    =    | 
COOH  COOH 

When  C02  is  anchored  to  the  amino-group,  carbamino-acids  are 
formed. 

,H 
CH2NH2  CH2N< 


+  C02  =   I  \COOH 

COOH  C( 


X)OH 

The  proteins  and  many  peptids  give  the  biuret  reaction  with  copper 
sulphate  in  alkali.  This  reaction  is  produced  by  all  substances  in 
which  two  CONH2  groups  are  united  to  a  carbon  or  nitrogen  atom 
or  to  each  other.    One  of  the  CONH2  groups  may  be  replaced  by  a 


32  THE  COMPOSITION  OF  FOODSTUFFS 

CH2NH2  or  a  CSNH2  group.  The  common  peptid  linking  presents 
the  appropriate  combination.  Most  polypeptids,  as  will  be  described, 
respond  to  the  biuret  test,  but  there  are  striking  exceptions  to  the 
rule,  as  in  the  case  of  the  resistant  antipoly peptid. 

It  is  not  contended  that  the  list  of  amino-acids  to  be  described  is 
complete.  Admitting,  however,  that  others  remain  to  be  discovered, 
those  at  present  known  are  certainly  the  most  important.  It  is  also 
not  true  that  the  amounts  stated  for  the  occurrence  of  the  different 
amino-acids  in  the  different  proteins  are  even  approximately  correct; 
the  figures  are  all  too  low.  The  methods  do  not  recover  the  full  yield, 
in  nearly  all  cases  the  loss  is  10  to  25  per  cent.;  in  the  case  of  some 
amino-acids,  as  serin,  the  loss  is  probably  one-half.  The  quantitative 
findings  will  be  given  later  in  a  summarized  table. 

Glycocoll  (glycin) 

CH2.(NH2) 

COOH 

This  is  amino-acetic  acid.  It  is  especially  derived  in  the  hydrolysis 
of  proteins  of  the  connective-tissue  group;  many  proteins  do  not  con- 
tain it.  Possessing  no  asymmetric  atom  of  carbon,  it  does  not  rotate 
the  plane  of  polarized  light.  In  the  proteins  that  contain  it,  it  seems 
to  be  firmly  or  centrally  bound,  and  is  not  easily  split  off. 

Alanin,  a-amino-propionic  acid. 

CH3 

CH.(NH2) 


A 


OOH 

This  substance,  while  found  in  many  proteins,  is  met  with  in  large 
amounts  in  the  connective-tissue  albuminoids.  Since  the  central 
atom  of  carbon  is  asymmetric,  alanin  rotates  the  plane  of  polarized 
light.  The  form  found  in  proteins  is  dextrorotatory.  Alanin  is  one 
of  the  most  important  of  the  amino-acids,  less  on  account  of  itself 
perhaps  than  on  account  of  other  amino-acids  that  are  derived  from 
it.  Such  are:  Phenylalanin,  tyrosin,  serin,  cystin,  tryptophan,  and 
histidin. 

Phenylalanin,  phenyl-a-amino-propionic  acid. 

CH 


HC        CH 
HC        CH 

y 


CH2 

coo 


(NH2) 
H 


THE  PROTEINS  33 

Alanin  in  which  a  hydrogen  in  the  methyl  group  has  been  replaced 
by  benzene.  It  is  present  in  the  levorotatory  form.  Phenylalanin 
is  present  in  small  amounts  in  nearly  all  proteins. 

Ty rosin,  p-oxy-phenyl-a-amino-propionic  acid. 

C.OH 
HC       CH 


HC       CH 


L 


CH.(NH2) 
OOH 


i 


Tyrosin  is  alanin  in  which  an  hydroxyl  group  is  combined  in  the 
benzene  neucleus  in  the  para  position  to  the  fatty  acid.  Present  in 
nearly  all  true  proteins,  it  is  absent  from  some  of  the  albuminoids. 
It  always  exceeds  alanin  in  amount.  Tyrosin  rotates  the  plane  of 
polarized  light  to  the  left.  Tyrosin  is  loosely  or  peripherally  combined 
in  the  protein  molecule  and  is  set  free  early  in  the  course  of  an  hydro- 
lysis. In  this  regard  it  is  very  different  from  alanin  and  phenylalanin, 
that  are  located  in  the  molecule  of  protein  in  a  manner  more  resistant 
to  hydrolysis. 

Serin,  a-amino-/3-oxy propionic  acid. 


CH2.(OH) 

CH.(NH2) 
COOH 


An  oxidation  derivative  of  alanin.  It  occurs  in  nearly  all  proteins, 
in  larger  amounts  than  usually  determined  on  account  of  difficulty  in 
isolation.  As  isolated  from  protein,  it  is  either  inactive  (racemic)  or 
rotates  the  plane  of  polarized  light  to  the  left.  Serin  is  not  easily  split 
off  in  the  hydrolysis  of  protein. 

Cystin,  a-diamino-|S-dithio-dilactylic  acid.  This  is  formed  by  the 
union  of  two  molecules  of  a  sulphur  derivative  of  alanin,  cystein, 
a-amino-jS-thio-propionic  acid. 


CH2.SH 

(NH2) 
30H 


A 


These  are  linked  by  the  two  sulphur  atoms  to  form  the  normal  cystin 
of  the  protein  molecule. 
3 


34  THE  COMPOSITION  OF  FOODSTUFFS 

H  H 

H— C— S      fH        H~1     S— C— H 


I      1  J      1      I 

(NHj).CH  CH.(NH2) 

COOH  COOH 

Cystin  is  found  in  nearly  all  proteins,  the  protamins  being  free  of 
it.  It  is  partially  broken  down  during  hydrolysis,  so  that  the  real 
amounts  are  greater  than  those  recovered.  The  cy stein  does  not  occur 
preformed  in  protein,  it  is  always  the  double  molecule.  Cystin  rotates 
the  plane  of  polarized  light  strongly  to  the  left.  The  cystin  of  protein 
and  the  cystin  of  renal  calculi  are  identical.  Cystin  is  derived  in  large 
amounts  especially  from  the  keratins.  It  is  probably  the  sole  form  of 
sulphur  in  most  proteins.  In  some  proteins,  however,  sulphur  seems 
to  exist  in  another  not  fully  identified  state.  There  is  some  evidence 
that  this  may  be  a-thio-lactic  acid. 


CH3 

(SH) 
)OH 


A 


The  cystin  is  closely  bound  in  the  molecule  of  protein  and  is  not 
easily  split  off. 

Tryptophan,  indol-a-amino-propionic  acid.  This  complex  sub- 
stance has  the  constitution 

CH 


Hi 


I  I 

C       CH        CH.(NH2) 


CH  NH  C 


OOH 


It  exists  in  nearly  all  proteins,  some  keratins  and  protamin  excepted. 
It  is,  like  tyrosin,  easily  split  off.  It  rotates  the  plane  of  polarized 
light  to  the  left. 

Histidin. — A  somewhat  related  body  is  histidin.  It  is  a-amino- 
jS-imidazol-propionic  acid. 


-NH 

-N 


I 

CH2 
i 


(NH,) 
30H 


THE  PROTEINS  35 

Histidin  is  present  in  nearly  all  the  higher  proteins.  It  is  intimately 
bound  in  the  centre  of  the  protein  molecule  and  resists  cleavage.  It 
rotates  the  plane  of  polarized  light  to  the  left.     It  is  strongly  basic. 

Aspartic  acid,  a-amino-succinic  acid. 

COOH 
CH2 

CH.(NH2) 


A 


OOH 

This  occurs  to  a  small  extent  in  animal  proteins,  and  to  a  much  greater 
extent  in  plants.  It  is  strongly  acid.  It  rotates  the  plane  of  polarized 
light  to  the  left.    Another  dicarboxylic  amino-acid  is 

Glutamic  acid,  a-amino-glutaric  acid, 

COOH 

I 
CH2 

I 
CH2 

I 
CH.(NH2) 

COOH. 

It  occurs  to  some  extent  in  animal  proteins,  in  large  amounts  in 
plants.  It  is  strongly  acid  and  rotates  the  plane  of  polarized  light  to 
the  right.  Both  aspartic  and  glutamic  acid  occur  widespread  in  plants 
in  the  form  of  the  amids,  asparagin,  and  glutamin. 

CO.(NH2)  CO.(NH2) 

CH2  CH2 

CH.(NH2)  6H2 

I  I 

COOH  CH.(NH2) 

COOH 

Whether  these  amids  occur  in  the  molecule  of  animal  protein  is  not 
known.     It  is  possible  that  some  of  the   ammonia   derived   in   the 
hydrolysis  of  protein  is  to  be  referred  to  them. 
Valin,  a-amino-iso valerianic  acid. 

CH3  CH3 


CH.(NH2) 
OOH 


i 


36  THE  COMPOSITION  OF  FOODSTUFFS 

This  substance  occurs  in  small  amounts  in  nearly  all  proteins.     It 
rotates  the  plane  of  polarized  light  to  the  right. 
Ornithin,  a-^-diamino-valerianic  acid. 

CH2.(NH2) 


CH2 
CH2 


CH.(NH2) 
COOH 

Ornithin  does  not  exist  preformed  in  protein,  but  only  in  combination 
with  urea  to  form  arginin.    It  is  basic  and  rotates  the  plane  of  polarized 
light  to  the  right. 
Leucin,  a-amino-isobutyl-acetic  acid. 

CH3  CH3 


CH 

I 

CH2 

CH.(NH2) 


A 


OOH 

Leucin  is  one  of  the  most  common  cleavage  products  of  protein, 
being  present  in  all  forms  above  protamin,  and  easily  split  off.  It 
rotates  the  plane  of  polarized  light  to  the  left.  A  somewhat  similar 
substance  is  isoleucin.     a-amino-/3-methyl,  /3-ethyl-propionic  acid: 

CH3    C2Il5 


CH 

CH.(NH2) 

COOH 

It  occurs  in  traces  in  many  proteins.    It  is  dextrorotatory. 

Prolin. — A  heterocyclic  amino-acid  is  prolin,  a-pyrrolidin-carboxylic 

acid. 

CH2 — CH2 


CH2    CH 


COOH 


It  occurs  widespread,  though  in  small  quantities,  as  a  rule,  being  present 
even  in  protamins.  It  is  strongly  levorotatory.  An  oxyprolin  is 
also  present,  but  its  constitution  is  not  understood.  It  is  also  strongly 
levorotatory. 


THE  PROTEINS 


37 


Lysin,  a-e-diamino-caproic  acid. 


Lysin  is  widely  distributed,  nearly  all  proteins  above  the  protamins 
contain  it.     It  is  strongly  basic.     It  is  dextrorotatory. 

Arginin  is  a  combination  of  the  already  described   ornithin   with 
a  guanidin  rest.     This  is  illustrated  in  the  equations: 


\ 


Urea 

/NH2 

O 
\NH2 


+ 


ornithin 


CH2.(NH2) 
+        CH2 


CH2 

CH.(NH2) 

COOH 


=        arginin  + 

NH2 

NH  =  C  —  NH 

CH2 

CH2 

CH2 


water 


H20 


CH.(NH2) 
COOH 


It  is  present  in  nearly  all  animal  and  vegetable  proteins,  and  like  lysin 
is  strongly  basic.  It  is  dextrorotatory.  Like  lysin  it  is  closely  bound 
in  the  protein  molecule,  and  is  not  easily  split  off. 

Ammonia. — All  proteins  above  the  protamins  contain  small  amounts 
of  ammonia.  Outside  of  arginin  (and  possibly  the  amids  of  aspartic 
and  glutamic  acids)  we  do  not  know  of  any  preformed  ammonia  in 
the  molecule.  Yet  it  seems  certain  that  it  is  not  originated  in  the 
reactions  of  hydrolysis.  Several  other  complex  amino-acids  have 
been  isolated  from  digestion  mixtures,  but  since  their  nature,  as  well 
as  their  constant  occurrence,  is  entirely  in  doubt,  they  cannot  concern 
us  in  a  discussion  of  metabolism.  Two  points  in  particular  require 
clarification:  The  nature  of  preformed  ammonia  and  the  nature  of 
sulphur  combinations  outside  of  cystin.  Bacteria  produce  ammonia 
from  amino-acids  and  considerable  ammonia  is  thus  evolved  in  normal 
digestion,  especially  in  the  colon.  There  is  no  evidence  that  ammonia 
is  formed  from  amino-acids  of  the  usual  type  by  hydrolysis. 

The  following  table  contains  the  figures  for  the  content  of  the  different 
proteins  in  amino-acids,  all  figures  being  as  stated  too  low.  When- 
ever figures  are  known,  they  are  given;  the  positive  presence  of  an 
amino-acid  is  indicated  with  a  plus  sign,  its  certain  negative  absence 


3S 


THE  COMPOSITION  OF  FOODSTUFFS 


with  a  negative  sign,  while  the  empty  spaces  indicate  that  the  question 
has  not  been  determined.  The  great  difficulty  of  adequate  purifica- 
tion of  the  proteins  submitted  to  hydrolysis  adds  to  the  complications. 


I 

2 

"3 

■ 

1 

|j 

1 

Proteins 

I 

1 

1 

I 

c 

> 

"3 

1 

+ 

a 
1 

1 

2 
I 

20 

i 

5 

3 
s 

I 

< 

3 

a 

1 

+ 

a 

I 

I 

2.3 

1 

1 

a 

I 

2. 

•a 

I 

- 
3. 

3. 

! 

Serum  albumin   . 

+ 

+ 

+ 

0 

Egg  albumin 

+ 

2 

2 

+ 

2 

8 

8 

2 

+ 

+ 

.2 

+ 

1. 

4. 

8. 

0 

Lac-albumin  .... 

+ 

+ 

+ 

+ 

1 

4 

19 

10 

1 

+ 

+ 

+ 

+ 

1. 

2. 

53. 

0 

Serum  globulin    . 

+ 

+ 

+ 

3 

18 

8 

2 

+ 

1. 

2. 

54. 

2. 

3.5 

Cotton-seed  edestin 

+ 

i 

11 

+ 

2 

2 

20 

6 

4 

+ 

i; 

+ 

1 

2. 

2. 

4. 

4. 

Sun-flower  edestin    . 

+ 

+ 

3 

13 

13 

3 

+ 

. . 

1 

2. 

4. 

4. 

2.5 

Globulin  from  toga-bean 

20 

3 

5 

i 

4 

9 

19 

4 

+ 

1.4 

2. 

4. 

1. 

Legumin 

5 

5 

i 

6 

9 

16 

4 

1. 

3. 

2. 

3." 

1. 

Gliadin 

*5 

0 

3 

+ 

2 

0 

36  1 

i.' 

2. 

+ 

+ 

2. 

2. 

53 

1. 

Zein 

3 

0 

1 

+ 

6 

IS 

18  1 

0 

+ 

+ 

3. 

5. 

2. 

0 

Hordein 

5 

0 

2 

9 

0 

33  + 

+ 

+ 

+ 

1. 

3. 

1. 

+ 

Glutin 

4 

2 

5 

+ 

4 

0 

23 

+ 

+ 

2. 

+ 

+ 

4. 

2. 

5. 

+ 

Leucosin 

1 

3 

6 

+ 

3 

11 

6 

3 

+ 

3. 

3. 

4. 

4. 

+ 

Avenin 

2 

5 

17) 

18 

4 

1. 

3. 

2. 

1. 

Fibrin 

+ 

4 

3 

1 

4 

17) 

10 

2 

+ 

+ 

i.' 

i 

3. 

3. 

4. 

3. 

Casein,  cow 

6 

5 

1 

+ 

3 

10 

11 

1 

1.5 

3. 

+ 

+ 

5. 

3. 

1. 

0 

Thymus,  histon  . 

7 

15 

1 

12 

+ 

2. 

5. 

2. 

3. 

+ 

Globin,  hemoglobin  . 

4 

5 

1 

2 

29 

2 

4 

+ 

11. 

.3 

i 

2. 

4. 

4. 

0 

Protamin,  salmon 

0 

0 

s7 

2 

0 

7 

0 

0 

0 

0 

0 

5 

0 

0 

0 

0 

Strurin 

12 

60 

0 

0 

0 

.. 

0 

13. 

0 

0 

0 

0 

+ 

0 

Scombin   . 

0 

0 

89 

0 

0 

4 

0 

0 

0 

0 

0 

0 

0 

0 

7. 

0 

Silk  fibroin 

0 

+ 

1  0 

+ 

0 

+ 

+ 

. . 

2 

10. 

1. 

2.1 

3.6 

Elastin 

+ 

1 

2 

21 

+ 

+ 

+ 

4. 

6. 

2.6 

Spongin    . 
Keratin 

+ 

+ 

.  . 

7 

is 

5 

.  . 

7.' 

+ 

0 

0 

14. 

+ 

.  . 

3 

5 

4 

IS 

3 

3 

5. 

3. 

1. 

+ 

Wool  keratin 

4 

12 

12 

2 

8.' 

+ 

0 

4. 

1. 

Gelatin 

3 

8 

1* 

8 

5 

2 

1 

+ 

0 

+ 

2. 

2. 

0 

.5 

1. 

16. 

Sugar  Content  of  Proteins. — An  important  question  concerns  the 
sugar  content  of  proteins.  Do  proteins  contain  preformed  sugar,  com- 
bined as  an  integral  part  of  the  molecule?  As  will  be  later  described, 
there  are  many  combinations  between  molecules  of  protein  and  mole- 
cules of  carbohydrate.  On  account  of  adsorption,  it  is  very  difficult 
to  free  proteins  of  carbohydrate  clinging  to  them.  But  as  the  materials 
are  analyzed,  it  is  becoming  clearer  that  in  the  direct  sense  sugar  is 
not  usually  a  component  of  protein.  So  far  as  we  know  at  present, 
there  is  but  one  form  in  which  sugar  is  present  preformed  in  the  protein 
molecule,  and  that  is  in  the  amino-sugar  glucosamin.  Many  proteins, 
especially  the  mucins,  contain  large  amounts  of  preformed  glucosamin 
that  is  hound  in  the  molecule  like  the  other  amino-acids.  Glucosamin, 
which  is  an  amino  derivative  of  glucose,  bears  a  striking  resemblance 
to  lysin  in  configuration  of  the  molecule. 


THE  PROTEINS  39 

Glucose  Glucosamin  Lysin 

CH2OH  CH2OH  CH2NH2 

CHOH  CHOH  CH2 

CHOH  CHOH  CH2 

CHOH  CHOH  CH2 

CHOH  CHNH,  CHNH, 

CHO  CHO  COOH 

The  molecule  of  glucosamin  is  to  be  regarded  as  directly  bound  in 
the  protein  molecule,  being  attached  by  its  NH2  group  to  the  COOH 
group  of  an  ammo-acid.  Since  it  has  itself,  however,  no  COOH  group, 
it  cannot  be  regarded  as  linked,  but  must  exist  as  a  terminal  group. 
The  mucins  and  related  proteins  may  contain  as  high  as  30  per  cent, 
of  glucosamin.  It  is  very  doubtful  if  the  stock  proteins  of  the  blood 
serum,  serum  albumin,  and  serum  globulin,  contain  any  glucosamin. 

The  Combination  of  Amino-acids  in  Protein. — The  proteins  being 
regarded  as  condensations  of  amino-acids,  how  are  we  to  picture  the 
internal  constitution  of  the  protein  molecule?  In  other  words,  after 
what  fashion  are  the  amino-acids  linked  or  bound?  This  question  is 
pertinent  not  only  to  the  problem  of  the  purely  chemical  construction 
of  protein,  but  also  to  problems  of  the  digestion  and  metabolism  of 
protein.  The  question  has  been  approached  from  the  inside  as  well 
as  from  the  outside,  through  synthesis  as  well  as  through  lysis,  and  the 
two  sets  of  data  are  very  harmonious  and  complementary.  Impor- 
tant really  are  two  phases  of  the  question:  (1)  How  are  the  amino- 
acids  bound  together,  and  (2)  can  we  regard  some  as  being  nuclear 
and  others  peripheral  in  their  location,  some  loosely  bound  and  others 
firmly  bound? 

Method  of  Linkage. — With  respect  to  the  method  of  linkage  of 
the  amino-acids,  our  definite  ideas  were  first  drawn  from  the  synthesis 
of  the  peptids.  Under  the  term  peptid  we  understand  simple  combi- 
nations of  amino-acids;  thus  we  have  di-,  tri-,  tetra-,  and  polypeptids, 
substances  containing  two,  three,  four,  or  many  molecules  of  ami  no- 
acid.  These  conceptions  have  been  confirmed  by  investigations  into 
native  proteins,  and  what  is  now  termed  the  peptid  linking  is  known 
to  be  the  method  of  combination  that  is  for  the  most  part  present  in 
native  proteins. 

This  peptid  linking  may  be  explained  as  follows:  Two  molecules 
of  glycocoll  may  be  united  to  form  a  dipeptid  termed  glycyl-glycin. 
This  peptid,  like  the  glycocoll,  has  a  free  carboxyl  and  free  amino- 
group,  it  is  amphoteric  and  presents  all  the  group  reactions  of  these 
two  groups.  Obviously,  therefore,  the  combination  of  the  two  mole- 
cules may  be  regarded  as  a  linking  of  the  carboxyl  group  of  one  mole- 
cule of  glycocoll  to  the  amino-group  of  the  other  molecule  of  glycocoll. 


40 
Thus: 


THE  COMPOSITION  OF  FOODSTUFFS 


CH2NH2       CH2NH2  CH2NH2 

CH2.NH— C  =  0       +      H20 
COOH 


v^xx2i>  xi2         ^xi2rN  r. 

I      +    1 

COOH  COOH 


or  to  make  the  illustration  linear: 

H  H  H 

H2N— C— COOH  +  H2N— C— COOH  =  H2N 

4  A 


H 

N— C— COOH  +  H20 

I      I 
H    O    H    H 


This  may  be  illustrated   for  a  tripeptid   in  the   following  equation 
Leucyl-glycyl-phenylalanin. 


Leucin                  + 

glycocoll 

+ 

phenylalanin 

CH3  CHj 

CH 

v 

/\ 

CH 

HC      CH 

CH2 

HC      CH 

H2N— C— H 

H 

Y 

4 

N— C— H 

A  A 

CH2 

1 

N— C— H 

1 

H    COOH 

This  tripeptid  presents  an  NH2  group  at  one  end  and  a  COOH  group 
at  the  other  end,  and  in  this  respect  acts  just  like  an  amino-acid.  It 
is,  of  course,  possible  to  have  in  a  peptid  larger  members  of  amino 
and  carboxylic  groups  when  diamino  and  dicarboxylic  acids  enter  into 
the  peptid.    This  may  be  illustrated  in  a  hypothetical  tetrapeptid: 


Leucin 


CH3  CH3 

Yn 

I 

CH2 

I 
H2N— C— H 


Phenylalanin 

CH 

/    \ 
HC  CH 

I  I 

HC  CH 

V 

CH2 

-N— C— H 
I       I 
H    C 

8 


Arginin 


Aspartic  acid 


HN 


NH2 

I 
C  — NH 

I 
CH2 

CH2 

I 
CH2 

I 
— N— C— H 

I       I 
H    C 

II 
O 


COOH 

CH2 

I 
N— C— H 

H    COOH 


THE  PROTEINS  41 

In  this  tetrapeptid  there  are  two  monamino-acids  and  two  diamino- 
acids.  The  molecule  contains,  therefore,  two  free  groups  of  NH2  and 
two  free  groups  of  COOH. 

The  possibilities  of  this  peptid  linkage  are  very  great,  and  no  less 
than  eighteen  molecules  of  amino-acid  have  been  synthetically  linked 
into  one  chain,  giving  a  polypeptid  of  the  molecular  weight  of  1213. 
At  the  same  time  it  is  obvious  that  the  molecules  of  native  protein 
can  hardly  be  made  up  of  such  simple  chains,  and,  indeed,  other  forms 
of  linkage  are  known. 

When  urea  and  ornithin  combine  to  form  arginin,  the  COOH  group 
of  the  ornithin  does  not  combine  with  the  NH2  group  of  the  urea; 
it  is  the  NH2  group  attached  to  the  ^-carbon  that  combines  with  the 
carbon  of  the  urea,  so  that  the  nitrogen  binds  two  carbons,  neither  of 
which  has  a  bond  attached  to  oxygen. 

NH2 
CH2NH2  HN=C--NH 

/NH2        CH2  CH2 

C=0  +  CH2       =  CH2         +      H20 

\NH2        <7HNH2  CH2 


COOH  CHNH2 

I 
COOH 

This  type  of  linkage  exists  so  far  as  known  only  in  the  union  of  urea 
and  ornithin.  It  is  a  very  firm  binding,  being  resistant  to  the  action 
of  steam  and  acid,  which  split  the  peptid  binding  with  ease.  It  is 
thus  adapted  to  serve  as  the  centre  of  a  chain,  as  the  keystone  of  an 
arch,  as  it  were.  In  addition  to  this,  arginin  presents  unusual  oppor- 
tunities for  attachment  of  other  amino-acids,  since  it  has  two  amino 
and  one  carboxylic  group. 

Another  form  of  binding  is  to  be  seen  in  cystin,  which  is  formed 
of  two  molecules  of  a-amino-/3-thio-propionic  acid. 

CH2SH         CH2SH  H  H 

CHNH2  +  CHNH2   =      H— C— S S— C— H 

COOH  COOH  H2NHC  CHNH2 

HOOC  COOH 

Like  the  binding  between  urea  and  ornithin,  this  linkage  is  obviously 
adapted  to  serve  in  the  centre  of  a  group,  to  either  side  of  which  two 
amino-acids  could  be  attached. 

These  are  the  only  form  of  linkages  definitely  known  to  exist  in 
the  protein  molecule.     But  it  were  shortsighted  to  assume  that  the 


42  THE  COMPOSITION  OF  FOODSTUFFS 

possibilities  of  combination  are  exhausted  in  these.  The  ammonia 
remains  in  arginin  suggest  another  form  of  binding,  nitrogen-to- 
nitrogen,  analogous  to  the  sulphur-to-sulphur  linkage  in  cystin.  In 
phenylalanin  the  benzene  ring  is  untouched  save  for  the  connection 
with  the  alanin;  in  tyrosin  there  is  an  hydroxyl  combined  with  the 
ring  in  the  para  position  to  the  amino-acid;  in  tryptophan  we  have 
indol  attached  to  the  fatty  acid.  It  is  certainly  possible  in  the  case  of 
phenylalanin  and  tyrosin  at  least  to  imagine  other  bindings  with  the 
benzene  ring;  that  there  are  other  possibilities  is  shown  in  direct  experi- 
ment. Peptids,  like  amino-acids,  bind  carbon  dioxid  and  give  the 
carbamino  reaction.  Now  in  the  case  of  amino-acids  it  is  only  the 
NH2  groups  that  bind  the  carbon  dioxid.  In  the  case  of  peptids  and 
proteins,  however,  not  only  the  NH2  groups  but  also  the  nitrogens  by 
which  the  amino-acids  are  bound  together  will  add  carbon  dioxid. 
It  is  theoretically  possible  that  ring  formations  of  the  type  of  piperazin 
may  exist  in  the  protein  molecule.  It  is  also  possible  that  the  oxy- 
acids  (serin  and  tyrosin)  might  form  esters.  Further  investigation 
will  make  these  clear  and  in  all  probability  indicate  additional  relation- 
ships. 

Groupings  in  Protein  Molecule. — When  now  we  come  to  consider 
the  manner  in  which  these  several  amino-acids  are  related  or  grouped 
in  the  huge  protein  molecule  by  the  different  bindings  that  have  been 
described,  we  approach  a  question  of  great  theoretical  importance. 
Investigations  in  the  disintegration  of  the  protein  molecule  by  steam, 
mineral  acids,  alkalies,  pepsin,  trypsin,  and  erepsin  have  taught  us  that 
certain  amino-acids  are  early  and  easily  split  off;  that  others  resist 
splitting;  that  some  may  be  split  off  by  acid  and  alkalies  that  cannot 
be  split  off  by  pepsin,  or  even  by  trypsin;  that  some  amino-acids  can- 
not be  recovered  until  the  protein  is  utterly  disintegrated.  These 
facts  will  be  detailed  under  the  appropriate  headings.  Here  they  interest 
us  only  because  they  prove  that  even  if  linked  together  in  the  same  way, 
some  amino-acids  are  refractory  to  hydrolysis,  others  yield  to  hydro- 
lysis. Among  those  that  are  very  easily  split  off  are  tyrosin,  trypto- 
phan, leucin,  and  ammonia.  Later  in  the  hydrolysis  leucin,  serin, 
cystin,  aspartic  acid  and  glutamic  acid  and  a  small  fraction  of  the 
diamino  bases  are  obtained.  Last  of  all  we  recover  glycocoll,  prolin, 
phenylalanin  and  the  rest  of  the  diamino  acids.  These  last  are  not 
recovered  by  tryptic  digestion,  and  constitute  what  has  long  been  known 
as  the  anti-peptone  fraction.  These  facts  suggest  that  certain  amino- 
acids  are,  so  to  speak,  peripheral  and  other  amino-acids  central  in 
location  within  the  molecule  of  protein. 

There  are  two  conceptions  of  these  relations  within  the  protein 
molecule.  One  corresponds  to  a  branched  chain;  the  other  to  linked 
groups  or  nuclei.  The  mere  fact  of  the  existence  of  the  diamino- 
and  dicarboxylic  acids  prevents  us  from  regarding  any  protein  as  a 
straight  chain,  like  the  synthesized  octadeca-peptid  composed  of  15 
molecules  of  glycocoll  and  3  of  leucin.     The  double  NH2  and  COOH 


THE  PROTEINS 


43 


groups  necessitate  a  branching.  Aspartic  and  glutamic  acid  have 
each  one  NH2  group  and  two  COOH  groups;  arginin  and  lysin  have 
each  one  COOH  and  two  NH2  groups;  the  other  amino-acids  in  protein 
have  one  group  of  each.  A  diagram  will  illustrate  the  branched  bind- 
ings. Let  the  sign  A  indicate  the  NH2  group,  the  sign  C  the  COOH 
group.  Assuming  the  centre  of  the  chain  to  be  composed  of  a  group 
of  glycocolls,  the  diamino-acids  would  cause  branchings  to  the  right 
while  the  dicarboxylic  amino-acids  would  cause  branchings  to  the 
left.    This  scheme  is,  of  course,  merely  diagrammatic  and  has  been  made 


--a 


±°w 


--AC-fl-AC||AC-f-A/ 


A  C-  A  C-  A  C-JA  C-fA  C-J-aN, „ ..- 

^L^L^JL^L^      (>  I A  Q  .A  c.  I A 

A  Of  A  cfA  OJA  G  A  C-A^1 " IL- 


A  O  -A 


C-  A  C 


"g|a  o|a  o^-a  c4a  c  — 


c-[a  o|a  c-|a  gj[a  Of-A  c-|a  c 


c]|a  c|a  c 
c-1- 


AC 


A  Gf  A  CM  -A  C  — 


symmetric.  It  illustrates,  however,  the  necessary  branching  that  must 
occur  as  the  result  of  the  presence  of  amino-acids  having  two  NH2 
or  COOH  groups,  and  corresponds  to  the  experimental  fact  that  many 
proteins  have  a  large  number  of  free  NH2  and  COOH  groups.  A  pre- 
ponderance of  the  diamino-acids  in  the  whole  molecule  would  lead 
to  a  basic  protein  like  protamin.  The  presence  of  a  preponderance 
of  the  dicarboxylic  acids  would  lead  to  an  acid  protein,  like  gliadin. 
It  is  more  than  doubtful  if  such  a  scheme  corresponds  to  the  full 
facts.  The  more  proteins  are  studied,  the  more  it  appears  that  within 
the  total  molecule  are  definite  groups,  and  it  is  the  linking  together 
of  these  groups  that  forms  the  completed  molecule.  This  view  is  gain- 
ing ground  for  the  reason  that  the  existence  of  such  groups  is  being 
demonstrated  in  different  proteins.  The  point  of  view  may  be  made 
clear  in  a  contemplation  of  the  protamins.  The  protamin  of  the 
salmon,  salmin,  contains  according  to  our  best  evidence  12  molecules 
of  arginin,  2  of  serin,  3  of  prolin,  and  1  of  valin.  Now  when  this  prota- 
min is  carefully  digested,  it  will  be  found  that  there  is  a  stage  midway 
between  the  original  state  and  complete  cleavage,  and  that  in  this 
stage  we  have  what  are  termed  protons — smaller  molecules  than 
protamin,  larger  than  the  amino-acids.  These  protons  are  known  to 
consist  each  of  two  molecules  of  arginin  with  one  of  monamino-acid. 
In  other  words,  salmin  when  hydrolyzed  first  breaks  up  into  six  mole- 
cules of  proton,  and  on  further  hydrolysis  each  molecule  of  proton 
breaks  up  into  three  molecules  of  amino-acids.    Thus: 


'  Arginin ' 

Serin 
Arginin  t 

— 

Arginin 

Serin 

1 
i  Arginin  ( 

— 

Arginin 
Prolin 
Arginin  t 

— 

Arginin' 

Prolin 

1 
:  Arginin  ( 

— 

Arginin 

Prolin 

1 
t  Arginin 

— 

Arginin 

1 
Valin 

i  Arginin  J 

44  THE  COMPOSITION  OF  FOODSTUFFS 

The  first  stage  of  hydrolysis  consists  in  the  cleavage  of  the  bindings 
between  the  six  diarginyls,  setting  these  (the  protons)  free.  Through 
hydrolysis  the  diarginyls  are  then  split  into  the  component  amino- 
acids.  This  is  quite  analogous  to  the  state  of  affairs  in  starch.  The 
hydrolysis  first  splits  the  molecule  of  starch  into  a  number  of  mole- 
cules of  maltose;  these  are  then  split  into  molecules  of  d-glucose. 
Investigations  with  other  proteins  have  yielded  identical  results. 

Conception  of  Protein  Molecule. — We  may  then  formulate 
our  conception  of  the  molecule  of  protein  as  follows: 

(a)  Native  proteins  are  to  be  regarded  as  linked  aggregates  of  poly- 
peptids,  these  forming  nuclei  or  groups  that  are  preformed  and 
intact  in  the  protein  molecule,  the  connection  of  polypeptid  to  poly- 
peptid  being  achieved  through  one  of  the  described  forms  of  linkage. 

(6)  Polypeptids  are  combinations  of  individual  amino-acids,  bound 
together  by  means  of  one  of  the  described  linkages. 

The  different  polypeptids,  as  well  as  the  molecule  of  native  protein 
itself,  are  variable  in  their  relations  to  pepsin,  trypsin,  and  erepsin. 
When  a  molecule  of  native  protein  is  digested,  the  groups  of  poly- 
peptids are  first  separated,  in  part  at  least;  these  then  react  toward 
the  ferment  in  accordance  with  their  own  properties,  some  being  refrac- 
tory, others  cleavable.  And  when  later  we  shall  say  of  erepsin  that 
it  does  not  digest  native  protein,  we  mean  that  it  cannot  attack  the 
bindings  between  the  polypeptids,  though  it  can  separate  the  individual 
amino-acids  in  a  polypeptid.  A  polypeptid  may  be  formed  as  a 
straight  or  branched  chain,  as  given  in  the  first  scheme.  Several  of 
these  sets  of  branched  chains  (polypeptids)  are  then  linked  to  form  a 
molecule  of  protein,  and  the  linkage  between  these  polypeptids  is  one 
of  relatively  easy  cleavage,  so  that  when  the  native  protein  is  sub- 
mitted to  hydrolysis,  these  are  first  separated.  Following  this  occur 
the  reactions  within  the  several  polypeptid  groups. 

This  composition  of  protein  makes  clear  the  most  extraordinary 
possibilities  of  isomerism.  It  is,  of  course,  true  that  not  all  proteins 
contain  all,  or  the  same,  amino-acids,  and  herein  lies  the  basis  of  much 
individualism  in  proteins.  When  proteins  contain  the  same  amino- 
acids  but  contain  them  in  different  amounts,  an  additional  basis  for 
individualism  exists.  But  even  when  proteins  contain  the  same  amino- 
acids  in  the  same  amounts,  the  possibilities  of  individualism  through 
true  isomerism  are  almost  innumerable.  In  the  simple  protamin, 
salmin,  composed  of  six  diarginyls,  a  large  number  of  isomers  are 
possible.  Serum  albumins  and  serum  globulins,  in  the  higher  animals, 
seem  to  have  identical  constituents;  but  they  are  very  different  sub- 
stances. And  finally,  stereoisomerism  affords  still  another  basis  of 
specialization.  Bearing  in  mind  the  premises  for  chemical  individualism 
in  proteins — difference  in  amino-acids,  difference  in  amounts  of  amino- 
acids,  simple  isomerism  and  stereoisomerism — let  us  consider  two 
groups  of  biological  facts  that  find  therein  their  explanation. 


THE  PROTEINS  45 

Disintegration  of  Protein  in  Digestion. — The  diet  of  animals,  be  they 
carnivora,  herbivora,  or  omnivora,  contains  many  kinds  of  protein. 
These  are  disintegrated  in  the  processes  of  digestion.  From  the  numer- 
ous products  of  the  digestion  of  these  diverse  proteins  the  body  forms 
two  stock  proteins,  the  serum  albumin,  and  serum  globulin  of  the  blood. 
The  diet  of  the  human  race  contains  probably  not  less  than  thirty  or 
forty  different  proteins,  occurring  in  amounts  large  enough  to  be  of 
importance  in  the  diet.  Yet  from  the  digestion  products  of  these  (the 
building  stones)  the  body  builds  the  two  stock  proteins  of  the  blood 
serum.  No  matter  how  varied  the  diet,  so  long  as  the  products  contain 
all  the  different  amino-acids,  the  body  builds  of  them  serum  albumin 
and  serum  globulin,  employing  the  four  factors  above  mentioned. 
The  human  body  contains  over  twenty  more  or  less  well-defined  pro- 
teins. These  are  all  formed  from  the  amino-acids  contained  in  the  two 
stock  proteins  of  the  blood.  In  the  tissues  concerned,  these  two  stock 
proteins  are  split  into  their  component  amino-acids,  and  from  these 
the  tissues  form  the  particular  protein  characteristic  of  this  or  that 
tissue;  some  amino-acids  are  rejected,  others  are  massed,  and  all  in 
all  an  internal  arrangement  is  effected  which  has  its  outward  mani- 
festation in  the  striking  variations  displayed  by  the  different  tissue 
proteins  of  the  body.  The  whole  maintenance  of  growth  rests  simply 
upon  the  faculty  of  building  specialized  structures  from  common 
building  stones — the  synthetic  function  of  tissues  lies  largely  in  design 
and  not  in  material.  It  is  this  fact  that  indicates  how  a  proper  vege- 
tarian diet  is  in  every  way  a  normal  and  competent  diet.  Plant  proteins 
contain  the  same  amino-acids  as  animal  protein  and  all  are  there  pre- 
sent in  abundance.  It  is  quite  immaterial  to  the  body  whether  it  forms 
its  two  stock  proteins  from  amino-acids  derived  from  plant  protein 
or  from  animal  protein.  Contrariwise,  it  is  equally  clear  that  animal 
protein  is  in  nowise  inferior  to  plant  protein. 

The  specialism,  however,  goes  much  farther  than  this.  Not  only 
does  the  animal  form  many  proteins  from  common  building  stones, 
it  also  places  upon  them,  or  rather  in  them,  its  biological  stamp.  It 
may  be  granted  that  the  caseins,  serum  albumins,  serum  globulins, 
hemoglobins,  and  other  proteins  have  the  same  percentage  composi- 
tions in  the  higher  animals,  they  are  isomers.  But  they  are  very  differ- 
ent substances  nevertheless,  as  the  now  enormous  literature  on  immuni- 
zation and  sensitation  with  foreign  proteins  positively  testifies.  Now 
the  only  conceivable  basis  for  this  biological  specificity  lies  in  isomerism. 
The  striking  differences  in  properties  displayed  by  isomers  is  well 
illustrated  in  the  hexoses.  This  is  for  the  hemoglobins  beautifully 
illustrated  in  their  properties  of  crystallization,  which  varies  for  each 
species.  The  number  of  possible  isomers  in  a  substance  like  serum 
globulin  runs  into  the  hundreds  of  thousands.  We  may,  therefore, 
feel  assured  that  in  the  isomerism  of  the  protein  molecule,  resting 
upon  the  intramolecular  arrangement  of  the  amino-acids,  we  have  a 
fully  adequate  basis  for  the  striking  biological  specificities  displayed 


46  THE  COMPOSITION  OF  FOODSTUFFS 

by  proteins.  Proved  this  hypothesis  is  not  and  cannot  be  until  the 
intramolecular  structure  of  the  proteins  is  available  for  analysis  and 
experimentation.  But  it  is  an  hypothesis  in  which  we  may  confidently 
believe. 

Scheme  for  Protein  Molecules. — If  now  we  add  to  our  knowledge  of 
the  protein  molecule  obtained  by  the  study  of  the  peptides  the  informa- 
tion derived  by  investigations  into  partial  and  completed  hydrolyses 
under  the  influence  of  acids,  alkalies,  steam,  and  the  several  ferments, 
we  are  in  a  position  to  erect  a  scheme  for  the  protein  molecule.  The 
first  stage  in  hydrolysis,  as  commonly  carried  out,  is  acid  protein  or 
alkali  protein.  These  compounds  represent  addition  products;  they 
are  formed  rapidly  near  the  temperature  of  the  coagulation  point 
of  the  proteins,  slowly  at  lower  temperature.  They  are  subject  to 
high  degrees  of  hydrolytic  dissociation.  Acids  and  alkalies  in  some 
way  render  the  proteins,  with  which  they  are  combined,  open  to  the 
attack  of  enzymes.  It  is  not  necessary  for  ferment  action,  however, 
that  proteins  be  combined  with  acid  or  alkali;  the  ferment  can  operate 
without  them,  though  slowly.  The  next  stage  is  that  of  the  proteose. 
There  have  been  many  proteoses  described,  as  there  have  been  many 
dextrins  described.  But  it  is  not  possible  to  demarcate  these  bodies, 
since  they  are  passing  into  each  other.  The  highest  proteose  may 
be  defined  as  the  protein  molecule  minus  one  peptone.  And  the 
successive  proteoses  are  apparently  due  to  the  successive  splitting  off 
of  peptones.  How  many  are  in  the  series,  we  do  not  know,  several 
certainly.  The  results  of  saltirig-out  procedures  do  not  and  cannot 
define  these  proteoses,  for  the  simple  reason  that  the  salting  out  of  a 
particular  proteose  is  modified  by  the  presence  of  other  proteoses 
and  of  peptone  in  the  system.  With  the  peptone  is  attained  the  stage 
when  a  neutral  salting-out  can  no  longer  be  accomplished.  When 
the  peptone  is  split,  apparently  polypeptids  are  set  free.  In  a  certain 
sense,  the  peptone  may  be  defined  as  a  poly  pep  tid.  The  cleavage 
of  the  polypeptid  sets  free  the  di-,  tri-,  tetrapeptids  and  free  amino- 
acids.  The  complete  hydrolysis  yields  only  free  amino-acids.  These 
polypeptids  are  not  of  one  order,  they  are  composed  in  part  of  different 
amino-acids,  and  they  present  very  different  degrees  of  resistance  to 
chemical  manipulations.  Steam  and  acids  split  them  all,  erepsin  and 
many  bacterial  ferments  split  them  all,  but  trypsin  is  unable  to  split 
some  of  them  and  pepsin  is  able  to  split  none  of  them.  These  resistant 
groups,  the  antipolypeptids,  suggest  themselves  as  the  nuclei  of  the 
peptones,  firmly  bound  and  thus  resistant  to  hydrolysis — the  centres, 
so  to  speak,  about  which  the  other  amino-acids  are  aggregated.  They 
are  not,  however,  present  in  all  peptones,  and  thus  we  have  in  the 
peptones  two  orders  of  magnitude  in  the  chemical  and  dynamic  sense. 
This  conception  of  the  molecule  may  be  put  into  a  scheme,  it  being,  of 
course,  borne  in  mind  that  many  of  the  details  are  arbitrary  and  that 
future  investigations  may  easily  result  in  pronounced  modifications. 


Peptone- 


Native 
Protein— >acid 
Protein 


Proteose 


THE  PROTEINS 

[  Peptid  — »amino-acids 

Polypeptid  \ 

[Amino-acids 

[  Peptid  — »amino-acids 

Polypeptid  j 

[Amino-acids 

f  Peptid  — ^amino-acids 

'Polypeptid  j 

[Amino-acids                                 \ 

Peptone 

[  Peptid  — ^amino-acids 

Polypeptid  \                                                                 xx    O 

( Amino-acids 

f  Peptid —^amino-acids                           ^^= 

Polypeptid  < 

[Amino-acids 

Peptone 

[  Peptid  — ►amino-acids 
Polypeptid  \ 

[Amino-acids 

[  Peptid  — »amino-acids 

[Polypeptid  < 

Proteose 

[Amino-acids 

Peptone] 

f  Peptid  — >amino-acids 

[Polypeptid  \ 

[Amino-acids 

[  Peptid  — >amino-acids 

Proteose 

[Polypeptid  < 

[Amino-acids 

Peptone] 

[Peptid  — >amino-acids 

[Polypeptid  j 

Amino-acids 

Proteose 

[  Peptid  — »amino-acids 

[Polypeptid  \ 

[  Peptid  ^amino-acids 

Peptone \ 

[Peptid— >amino-acids 

[Polypeptid  \ 

[  Peptid  — >amino-acids 

17 


H 


Concerning  the  natural  peptids  that  are  resistant  to  ferment  action 
we  possess  data  drawn  from  various  sources.  There  are  two  groups 
resistant  to  the  action  of  trypsin.  One,  which  gives  the  biuret  reaction, 
yields  on  hydrolysis  after  isolation  prolin,  glycocoll,  alanin,  phenyl- 
alanin,  leucin,  aspartic  and  glutamic  acids.  One  antipolypeptid 
prepared  from  gelatin  contains  argenin,  lysin,  glycocoll,  and  glutamic 
acid.  If  proteins  be  carefully  hydrolyzed  with  dilute  acid,  it  is  possible 
to  check  the  process  at  a  stage  when  resistant  basic  groups  can  be 
isolated.  These  have  been  termed  kyrins.  These  kyrins  are  com- 
posed of  arginin,  lysin,  histidin,  glutamic  acid  and  glycocoll.  Belong- 
ing to  this  group  of  substances  apparently  is  the  long  known  oxy- 
proteinic  acid.  This  substance,  which  may  be  regarded  as  normal 
in  the  urine,  has  been  shown  on  hydrolysis  to  yield  alanin,  leucin, 
phenylalanin,  glutamic  acid,  and  glycocoll. 

In  the  products  of  the  enzymic  hydrolysis  of  protein  many  peptids 
have  been  found  that  are  identical  with  peptids  synthesized  from 
amino-acids,  a  finding  of  the  most  impressive  kind.  In  the  building- 
up  of  peptids  large  molecules  have  been  constructed  that  give  most  of 
the  reactions  of  peptones;  they  are  digestible  with  trypsin  and  erepsin, 
some  may  even  be  salted  out  like  proteoses.  It  is  this  success  of  syn- 
thesis, together  with  the  isolation  from  digestion  products  of  the  same 
peptids  that  have  been  synthesized  in  the  laboratory,  that  make  us 


48  THE  COMPOSITION  OF  FOODSTUFFS 

so  certain  that  our  present  conceptions  of  the  intramolecular  constitu- 
tion of  protein  are  correct,  and  lead  to  the  conviction  that  proteins 
in  all  respects  identical  with  native  proteins  will  ere  long  be  synthesized 
in  the  laboratory.  The  peptids,  known  through  synthesis,  that  have 
been  recovered  from  digestion  products  include  the  following:  Glycyl- 
alanin,  glycyl-leucin,  glycyl-tyrosin,  glycyl-valin,  alanyl-leucin,  alanyl- 
prolin,  alanyl-glycin,  leucyl-glutamic  acid,  leucyl-alanin,  and  prolin- 
phenylalanin. .  In  addition  the  following  more  complex  peptids  have 
been  recovered :  Glycocoll-alanin-tyrosin,  leucin-tyrosin-glycocoll, 
cystin-tyrosin-glutamic  acid,  tryptophan-glutamic  acid,  and  trypto- 
phan-leucin-glutamic  acid.  In  this  connection  it  is  interesting  to 
note  that  the  synthetic  peptids  that  are  digestible  with  trypsin  in 
vitro,  are  completely  digested  and  bound  in  the  tissues  when  introduced 
intraveneously. 

Tryptophan  and  tyrosin  seem,  in  a  certain  sense,  to  render  a  protein 
susceptible  to  salting-out;  at  least,  the  proteoses  seem  to  cease  to  be 
precipitajble  by  salting-out  in  proportion  to  the  splitting  off  of  their 
tyrosin  and  tryptophan.  On  the  other  hand,  there  are  relatively  simple 
peptids  containing  these  amino-acids  in  large  amount  that  can  be 
salted  out  from  solution.  Of  the  size  of  the  peptones  we  know  very 
little.  One  peptone  isolated  from  silk  fibroin  seemed  to  consist  of 
2  glycocoll,  1  d-alanin,  and  1  1-tyrosin.  It  is,  however,  as  stated, 
certain  that  there  are  peptones  of  large  size  with  peptid  properties; 
while  there  are  tripeptids  with  many  of  the  qualities  of  proteose. 
The  properties  depend  not*  only  on  the  size  of  the  molecule,  but  also 
and  largely,  on  the  component  amino-acids,  and  their  linkage. 

Certain  amino-acids  seem  to  be  located  or  concentrated  in  one  of 
the  peptones  of  a  protein;  this  holds  especially  for  cystin  and  trypto- 
phan. In  some  proteins,  however,  there  seems  to  be  two  fractions  of 
tryptophan,  one  is  split  off  early  while  one  appears  late. 

If  we  observe  the  qualitative  march  of  an  hydrolysis  from  day  to 
day,  we  will  observe  a  certain  general  order  in  the  appearance  of  the 
amino-acids  quantitatively.  The  earliest  to  appear  are  tyrosin,  cystin, 
and  tryptophan.  Then  gradually  appear  leucin,  alanin,  valin,  aspartic 
and  glutamic  acids.  Next  appear  the  bases  and  histidin.  Prolin  and 
phenylalanin  do  not  appear  free  in  a  tryptic  digestion  at  all.  They 
appear  last  of  all  in  an  ereptic  digestion,  with  the  final  fraction  of 
diamino-acids  and  glycocoll. 

Caloric  Value. — The  caloric  value  of  different  proteins  varies  from 
5.5  to  6  Cal.  The  heat  value  in  the  animal  body  is  of  course  lower, 
the  metabolizable  energy  of  protein  averaging  3.9  Cal.  for  plant  protein, 
and  4.3  Cal.  for  animal  protein. 

FOODSTUFFS    IN    THE   DIET 

Do  the  descriptions  of  the  foodstuffs  from  the  standpoint  of  carbo- 
hydrate, fat,  and  protein  exhaust  the  chemical  possibilities  of  a  diet? 


FOODSTUFFS  IN  THE  DIET  49 

Are  there  other  features  of  the  foodstuffs  that  lie  without  the  qualities 
of  carbohydrate,  fat,  and  protein?  Can  an  organism  subsist  on  pure 
sugar,  fat,  and  protein?  Four  further  factors  must  be  considered,  one 
quite  obvious,  the  others  as  yet  intangible.  Inorganic  salts  are,  of 
course,  needed  in  a  diet,  since  certain  salts  and  ions  are  essential  to  the 
physico-chemical  constitution  of  cells  and  tissues.  The  now  apparently 
demonstrated  relation  between  the  occurrence  of  beri-beri  and  the 
consumption  of  polished  rice  supposedly  furnished  an  illustration  of 
the  need  of  equilibrium,  as  well  as  plenty,  in  inorganic  ions.  The 
defect  in  the  polishing  of  rice  that  is  operative  in  the  etiology  of  beri- 
beri is,  however,  not  inorganic  but  organic,  diffusible  and  non-colloidal. 
The  second  factor  lies  in  the  state  of  conservation  of  the  foods.  Indi- 
viduals nourished  on  conserved  foods  acquire  scurvy.  Infants  fed 
on  boiled  milk  do  not  maintain  their  nutrition  normally.  The  use  of 
fresh  vegetables,  especially  potatoes  and  the  citrus  fruits,  will  prevent 
the  occurrence  of  scurvy  and  cure  it  after  it  has  set  in.  Under  these 
circumstances  it  was  inferred  that  certain  thermolabile  organic  acids 
were  in  some  way  essential  to  metabolism.  How  labile  were  these 
assumed  substances  may  be  realized  when  it  is  recalled  that  the  freezing 
of  the  potato  robs  it  of  its  antiscorbutic  properties.  This  point  of 
view  became  untenable,  however,  when  upon  one  of  the  Antartic 
expeditions  the  observation  was  made  that  fresh  meat  was  as  effective 
an  antiscorbutic  as  fresh  vegetables  or  lime  juice.  There  is  apparently 
some  change  that  follows  cooking,  some  circumstance  attending  the 
conservation  of  foods  that  disturbs  an  essential  factor  in  normal  nutri- 
tion. Thirdly,  the  nutrition  of  sterile  animals  fed  on  sterile  food  (in 
a  word,  digestion  without  bacteria)  is  not  normal.  We  possess  no 
concrete  idea  of  this  fact,  we  do  not  know  whether  bacteria  contribute 
necessary  substances,  whether  they  in  some  way  modify  the  processes 
of  digestion  or  in  what  manner  this  apparently  indispensable  action 
is  attained.  Man  is  apparently  a  symbiotic  organism,  though  it  will 
hardly  be  possible  to  attain  greatly  advanced  age  through  the  con- 
sumption of  any  particular  strain  of  microorganisms.  Bacteria  are 
plants  and  it  has  been  inferred  that  possibly  all  they  contribute  could 
be  found  in  raw  plants.  Vegetable  fiber  is  indeed  valuable,  and  plants 
probably  contain  all  the  chemical  ingredients  of  bacteria.  Yet  the 
relation  seems  less  tangible  than  this. 

The  final  consideration  affecting  the  total  adaptability  of  a  food  or 
ration  lies  in  the  source  of  the  foods.  It  will  be  made  clear  in  the  dis- 
cussion of  the  minimum  nitrogen  input  that  proteins  in  different  foods, 
even  when  containing  all  the  requisite  amino-acids,  vary  in  their  powers 
of  covering  the  needs  of  the  tissues.  But  more  striking  even  are  the 
variations  to  be  noted  in  particular  rations  that  are  balanced  in  every 
chemical  respect,  both  for  protein  and  caloric  values.  Thus  it  has  been 
shown  by  careful  feeding  experiments  extending  over  several  years, 
that  a  ration  drawn  solely  from  the  wheat  plant,  including  the  grain, 
is  not  adapted  to  the  normal  growth  and  functionation  of  cattle,  while 
4 


50 


THE  COMPOSITION  OF  FOODSTUFFS 


an  otherwise  comparable  ration  drawn  solely  from  the  maize  plant 
is  fully  adapted  to  all  the  needs.  Heifers  raised  on  the  wheat  plant 
are  inferior  in  size  and  strength,  the  offspring  are  inferior  and  the  milk 
secretion  is  below  the  normal.  This  could  not  have  been  due  to  the 
protein,  the  carbohydrates,  fats,  or  to  the  ash;  so  far  as  can  be  deter- 
mined, it  lies  in  some  as  yet  unknown  factor.  It  is  interesting  to  com- 
pare this  observation  in  cattle  with  the  widespread  conviction  that 
in  man  maize  cannot  be  used  to  replace  wheat,  oats,  or  barley  in  the 
bread  ration. 

The  three  factors  mentioned  do  not  seem  operative,  in  the  experi- 
mental sense,  in  short  diet  tests.  But  they  must  never  be  overlooked 
in  prolonged  diet  tests,  or  in  the  statistical  attempt  to  estimate  the 
diet  relations  of  a  group  or  race  of  people. 

The  following  tables  contain  the  food  values  for  many  raw  and 
cooked  foods.  The  figures  are,  of  course,  approximate  only,  and  the 
analytical  values  will  fluctuate  with  the  grade  of  foodstuff  and  also 
with  the  method  of  cooking.     (Modified  from  Atwater.) 


"3 

J 

Edible  portion 

Available  nutrients 

£S 

Food 

£m 

00 

i 

S 

11 

1  a 

B 

3§ 

.9 
'53 

1 

o5 

a-8 

1 

a 

£ 

p 

(X, 

fa 

o 

o 

Animal  foods — Beef  (fresh) 

% 

% 

% 

% 

% 

% 

% 

Brisket 

23.3 

54.6 

2.1 

15.3 

27.1 

.7 

325 

Chuck     .      .      . 

16.3 

62.7 

1.8 

17.9 

17.1 

.7 

242 

Flank      .      .      . 

10.2 

60.2 

1.9 

18.3 

19.9 

.7 

270 

Loin,  lean     . 

13.1 

67.0 

1.2 

19.1 

12.1 

1.0 

199 

Loin,  medium 

13.3 

60.6 

1.8 

17.9 

19.2 

.8 

262 

Loin,  fat 

10.2 

54.7- 

1.9 

17.0 

26.2 

.9 

325 

Neck 

. 

27.6 

63.4 

1.6 

19.5 

15.7 

.7 

230 

Plate       .      .      . 

16.5 

54.4 

2.2 

16.0 

27.6 

•  6 

330 

Ribs  .... 

. 

20.8 

55.5 

2.0 

17.0 

25.3 

.7 

315 

Round,  lean 

8.1 

70.0 

1.0 

20.7 

7.5 

1.1 

160 

Round,  medium 

7.2 

65.5 

1.6 

19.7 

12.9 

.8 

210 

Round,  fat   . 

12.0 

60.4 

1.6 

18.9 

18.5 

1.0 

260 

Round,  second  cut 

19.5 

69.8 

1.3 

19.8 

8.2 

.8 

170 

Rump 

20.7 

56.7 

2.0 

16.9 

24.2 

.7 

305 

Foreshank    . 

36.9 

67.9 

1.4 

19.8 

11.0 

.7 

190 

Tongue   . 

26.5 

70.8 

1.3 

18.3 

8.7 

' 

.8 

165 

Shoulder  and  clod 

16.4 

68.3 

1.5 

19.0 

10.7 

' 

.8 

185 

Fore  quarter 

18.7 

60.4 

1.8 

17.4 

20.3 

.7 

265 

Hind  quarter 

15.7 

59.8 

1.8 

17.8 

20.5 

.7 

270 

Side,  lean      . 

19.5 

67.2 

1.3 

18.7 

12.5 

.9 

210 

Side,  medium 

17.4 

59.7 

1.8 

17.6 

20.9 

.7 

270 

Side,  fat 

13.2 

47.8 

2.5 

15.7 

34.6 

.5 

408 

Liver 

7.0 

71.2 

1.2 

20.4 

4.3 

1 

7 

1.2 

137 

Suet  (unrendered  tallow) 

13.7 

4.3 

4.6 

77.7 

.2 

760 

Hind  shank  .... 

53^9 

67.8 

1.4 

20.3 

10.9 

.7 

.190 

FOODSTUFFS  IN  THE  DIET 


51 


Food 


Animal  foods. 

Beef  (preserved  and  cooked). 

Veal  (fresh) 


Breast     . 

Chuck     .      . 

Cutlets  (round) 

Flank      .      . 

Leg    .      .      . 

Loin  . 

Neck 

Rib    .      .      . 

Shank 

Fore  quarter 

Hind  quarter 

Side   .      .      . 

Liver 


Lamb  (fresh) 


Breast  or  chuck 
Leg    .      .      . 
Loin  . 
Neck 
Shoulder 
Fore  quarter 
Hind  quarter 
Side  .      .      . 


Mutton  (fresh) 


Chuck 
Flank 


8S 

?8 


32 


% 


21.3 

18.9 

3.4 


14 
16 
31 
24 
62 
24 
20 


22.6 


19.1 
17.4 
14.8 
17.7 
20.3 
18.8 
15.7 
19.3 


21.3 
9.9 


Edible  portion 


% 


66.0 
73.0 
70.7 
68.9 
70.0 
69.0 
72.6 
72.7 
74.5 
71.7 
70.9 
71.3 
73.0 


56.2 
63.9 
53.1 
56.7 
51.8 
55.1 
60.9 
58.2 


50.9 
46.2 


si  (3 
—  O 


% 


1.5 
1.1 
1.3 
1.3 
1.3 
1.3 
1.1 


2.0 
1.7 
2.2 
1.9 
2.2 
2.0 
1.8 
2.0 


2.4 
2.6 


% 


18.9 
19.1 
19.7 
19.9 
19.6 
19.3 
19 
20 
20 
19 
20 
19.6 
9.7 


18.5 
18.6 
18.1 
17.2 
17.6 
17.8 
19.0 
17.1 


14.6 
14.7 


Available  nutrients 


i 

0 

00 

E 

1 

I 

1 

% 

% 

% 

13.3 

.8 

6.2 

.8 

7.3 

.8 

9.9 

.8 

8.6 

.9 

10.3 

.8 

6.6 

.8 

5.8 

.8 

4.4 

.8 

7.6 

.7 

7.9 

.8 

7.7 

.8 

5.0 

1.0 

22.4 

.8 

15.7 

.8 

26.9 

.8 

23.6 

.8 

28.2 

.8 

24.5 

.8 

18.1 

.8 

21.9 

.8 

31.9 

.7 

36.4 

.5 

-§ 


210 
140 
155 
180 
170 
180 
150 
145 
130 
160 
165 
160 
90 


295 
230 
335 
300 
345 
310 
255 
285 


370 
410 


52 


THE  COMPOSITION  OF  FOODSTUFFS 


Food 


Animal  foods. 

Poultry  and  game  (cooked  and 

canned). 

Fish  (fresh) 


Bass,  black,  whole 
Bluefish  . 
Codfish,  dressed 
Cod  steaks   . 
Flounder,  whole 
Haddock 
Halibut  steak 
Lake  trout    . 
Mackerel 
Weakfish 
Whitefish,  whole 


Shell  fish  (fresh) 

Long  clams,  in  shell 
Round  clams,  in  shell 
Oysters,  in  shell 
Oysters,  solids   . 
Clams,  round,  solids 
Crabs,  hard  shells   . 
Lobster  .... 


Fish  (preserved  and  canned) 


Cod,  salt       .      .      .      . 
Cod,  salt,  boneless  . 
Halibut,  smoked 
Herring,  smoked 
Mackerel,  salt,  dressed 
Salmon,  canned 
Sardines,  canned     . 
Lobster,  canned 
Clams,  canned  . 
Oysters,  canned 


% 

54.8 
48.6 
29.9 
9.2 
61.5 
51.0 


17. 
48. 
44. 
51. 
53. 


41.9 
67.5 
81.4 


52.4 
61.7 


24.9 
1.6 
7 

44 

19 

14 

5 


Edible  portion 


% 

76.7 

78.5 
58.5 
79.7 
84.2 
81.7 
75.4 
70.8 
73.4 
79.0 
69.8 


85.8 
86.2 
86.9 
88.3 
80.8 
77.1 
79.2 


53.5 
55.0 
49.4 
34.6 
43.4 
63.5 
52.3 
77.8 
82.9 
83.4 


—   V 

•3-C 


% 

1.0 

1.0 

.5 

.9 

.7 

.8 

1.1 

1.3 

1.3 

.9 

1.4 


1.0 

.9 

.8 

.6 

1.0 

1.4 

1.1 


6.8 
5.5 


3.1 
1.3 
1.0 

.8 


Available  nutrients 


% 

20.0 
18.8 
10.8 
18.1 
13.8 
16.7 
18.0 
17.3 
18.1 
17.3 
22.2 


8.3 
6.3 
6.0 

5.8 
10.3 
16.1 
15.9 


20.9 
24.9 
20.1 
35.8 
16.8 
21.1 
22.3 
17.6 
10.2 
8.5 


% 

1.6 

1.1 

.2 

.5 

.6 

.3 

4.9 

9.8 

6.7 

2.3 

6.2 


.9 
.4 
1.1 
1.2 
1.0 
1.9 
1.7 


.3 

.3 

14.3 

15.0 


25 

11 

is 

1 


% 


.9 

1.0 

.6 

.9 

1.0 

.9 

.8 

.9 

.9 

.9 

1.2 


2.0 
2.0 
1.5 
.8 
1.7 
2.3 
1.7 


18.5 
14.3 
11.3 
9.9 
9.7 
2.0 
4.2 
1.9 
2.1 
1.1 


•So 


105 

95 

50 

85 

65 

75 

126 

170 

145 

100 

160 


53 
45 
50 
50 
75 
95 
90 


95 

110 

225 

300 

310 

205 

275 

90 

65 

75 


FOODSTUFFS  IN  THE  DIET 


53 


Food 


Vegetable  foods. 
Cereals,  etc. 

Flour: 

Family  and  straight  grade 

High  grade     .... 
Wheat  preparations: 

Breakfast  foods   . 

Macaroni  .  .      . 

Macaroni,  cooked 

Spaghetti 

Noodles 

Bread : 

Brown 

Corn  (Johnnycake)   . 

Rye 

Graham 

Whole  wheat 

White  wheat  .... 

Biscuit,  baking  powder  . 

Rolls 

Toasted  bread     . 
Crackers : 

Boston  (split) 

Milk,  cream    .... 

Graham 

Oysters 

Soda 

Water 

Cakes,  cookies,  etc.: 

Bakers'  cake  .... 

Coffee  cake     .... 

Gingerbread  .... 

Sponge  cake  .... 

Drop  cake      .... 

Molasses  cookies 

Sugar  cookies 

Ginger  snaps  .... 

Wafers 

Doughnuts     .... 
Pie,  pudding,  etc.: 

Pie,  apple 

Pie,  custard    .... 

Pie,  squash     .... 


% 


<B   ft 

a 


% 


Edible  portion 


% 


12.8 
12.4 

9.6 
10.3 
78.4 
10.6 
10.7 

43.6 
38.9 


35 
35 
38 
35 
22 
29 


24.0 

7.5 
6.8 
5.4 
4.8 
5.9 
6.8 

31.4 

21.3 

18.8 

15.3 

16.6 

6.2 

8.3 

6.3 

6.6 

18.3 

42.5 
62.4 
64.2 


a  o 
P 


% 


4.0 
4.0 

4.5 
4.5 
1.3 
4.0 
4.2 

2.8 
3.5 
3.4 
4 
2 
3 
7 
6 
1 


5.0 
5.0 

4.8 
5.4 
4.9 
5.0 

3.3 
3.8 
4.3 
4.4 
4.5 
4.7 


3.1 
2.2 

2.4 


Available  nutrients 


% 


8.3 

8.7 

9.3 
10.4 
2.3 
9.4 
9.1 


7.2 
6.9 
8.9 

8.5 
7.5 
7.7 
8.8 
7.6 
8.3 

4.8 
5.5 
4.5 
4.8 
5.9 
5.6 
5.4 
5.0 
6.7 
5.2 

2.4 
3.2 
3.4 


% 


1.0 
.9 

1.6 
.8 

1.4 
.4 
.9 


1 

12 

3 

1. 


7.7 
10.9 
8.5 
9.5 
8.2 
7.9 

4.1 
6.8 
8.1 
9.6 

13.2 
7.8 
9.2 
7.7 
7.7 

18.9 

8.8 
5.7 
7.6 


02 

a; 

if 

V 

m 
< 

% 

% 

73.5 

A 

73.6 

A 

74.0 

1.0 

73.0 

1.0 

15.6 

1.0 

75.1 

.5 

74.3 

.8 

46.2 

1.6 

45.2 

1.7 

52.0 

1.1 

51.3 

1.1 

49.1 

1.0 

j  52.3 

.8 

51.8 

1.1 

55.8 

.8 

60.3 

1.3 

69.9 

1.4 

68.5 

1.3 

72.5 

1.1 

69.3 

2.2 

71.8 

1.6 

70.6 

1.4 

55.8 

.6 

61.9 

.7 

62.1 

2.2 

64.5 

1.4 

59.2 

.6 

74.0 

1.7 

71.6 

1.0 

74.3 

2.0 

73.0 

1.2 

52.1 

.7 

41.8 

1.4 

25.7 

.8 

21.4 

1.0 

s 


355 
355 

365 
360 
90 
360 
360 

230 
260 
260 
265 
255 
270 
360 
300 
310 

405 
425 
420 
420 
415 
410 

295 
350 
360 
380 
400 
410 
410 
410 
410 
440 

265 
175 
175 


54 


THE  COMPOSITION  OF  FOODSTUFFS 


I 

1 

a 

Edible  portions 

Available  nutrients 

Food 

I 
I      | 

4m 
11 

Si 

a 
3 

1 

it 

A 

I 

a          * 

«« 

S 

* 

%■* 

i 

-52 

H 

£ 

p 

£ 

fi 

u 

U 

Vegetable  foods. 

Vegetables 

^ 

% 

% 

% 

% 

% 

% 

Peas,  green 

45 

74.6 

2.2 

5.2 

.5 

16.7 

.8 

95 

Peas,  green,  cooked 

73.8 

2.5 

5.1 

3.1 

14.4 

1.1 

105 

Potatoes 

20 

78.3 

1.4 

1.7 

.1 

17.7 

.8 

80 

Potatoes,  cooked,  boiled    . 

75.5 

1.7 

1.9 

.1 

20.0 

.8 

90 

Potatoes,  mashed  and  creamed 

75.1 

2.0 

2.0 

2.7 

17.1 

1.1 

105 

Pumpkins 

50 

93.1 

.6 

.7 

.1 

5.0 

.5 

25 

Radishes 

30 

91.8 

.7 

1.0 

.1 

5.6 

.8 

25 

Rhubarb 

40 

94.4 

.6 

.4 

.6 

3.5. 

.5 

20 

Squash    . 

50 

88.3 

.9 

1.1 

.5 

8.6 

.6 

45 

Spinach,  fresh 

92.3 

1.0 

1.6 

.3 

3.2 

1.6 

20 

Spinach,  cooked 

89.8 

1.1 

1.6 

3.7 

2.7 

1.1 

50 

Sweet  potatoes,  fresh   . 

20 

69.0 

2.1 

1.3 

.6 

26.2 

.8 

125 

Sweet  potatoes,  cooked 

51.9 

3.0 

2.2 

1.9 

40.3 

.7 

195 

Tomatoes 

94.3 

.4 

.7 

.4 

3.8 

.4 

20 

Turnips 

30 

89.6 

.8 

1.0 

.2 

7.8 

.6 

35 

Vegetables  (canned) 

Asparagus 

94.4 

.6 

1.2 

.1 

2.8 

.9 

20 

Beans,  baked 

68.9 

2.7 

4.8 

2.3 

19.7 

1.6 

125 

Beans,  string 

93.7 

.7 

.8 

.1 

3.7 

1.0 

20 

Beans,  lima 

79.5 
76.1 
85.3 

1.7 
1.7 
1.4 

3.0 
2.1 

2.7 

.3 
1.1 

.2 

14.3 

18.3 

9.6 

1.2 

.7 
.8 

75 

Sweet  corn 

100 

Peas,  green 

50 

Succotash     

75.9 
94.0 

1.8 
.5 

2.7 
.9 

.9 
.2 

18.0 
3.9 

.7 
.5 

100 

Tomatoes 

20 

Fruits,  etc.  (fresh) 

Apples 

25 

84.6 

1.6 

.3 

.5 

12.8 

.2 

60 

Apricots 

6 

85.0 

1.5 

.9 

12.2 

.4 

55 

Bananas 

35 

75.3 

2.7 

1.0 

5 

19.9 

.6 

100 

Blackberries 

86.3 

1.5 

1.0 

9 

9.9 

.4 

55 

Cherries  . 

5 

80.9 

2.0 

.8 

7 

15.1 

.5 

70 

Cranberries  . 

88.9 

1.2 

.3 

5 

8.9 

.2 

40 

Currants 

85.0 

1.7 

1.2 

11.6 

.5 

50 

Figs   .      .      . 

79.1 

2.2 

1.2 

17.0 

.5 

75 

Grapes    . 

25. 

77.4 

2.4 

1.1 

i 

4 

17.3 

.4 

90 

Huckleberries 

81.9 

2.0 

.5 

5 

14.9 

.2 

70 

Lemons  . 

30 ' 

89.3 

1.2 

.8 

6 

7.7 

.4 

40 

Muskmelons 

50 

89.5 

1.1 

.5 

8.4 

.5 

35 

Oranges  . 

27. 

86.9 

1.4 

.6 

2 

10.5 

.4 

45 

CHAPTER    II 

THE  THEORY  OF  FERMENT  ACTION 

Fermentations  are  to  be  regarded  as  accelerations  of  existing  reac- 
tions. As  accelerations  of  existing  reactions  they  are  classed  with  the 
reactions  of  catalysis.  In  every  reacting  system  there  is  a  driving 
force  and  a  passive  resistance  to  the  reaction.  Anything  that  will 
lower  this  passive  resistance  will  accelerate  the  reaction  velocity. 
The  catalyzer  is  related  only  to  the  condition  of  passive  or  internal 
resistance.  The  positive  catalyzer  and  increase  in  temperature  both 
act  by  reduction  in  the  internal  resistance.  The  modus  operandi  of 
catalytic  acceleration  is  in  general  defined  as  a  succession  of  inter- 
mediary reactions — a  definition  that  applies  directly  only  to  reactions 
in  a  homogeneous  system.  Fermentations  are  to  be  considered  as 
limited  and  reversible  reactions.  There  is  no  known  essential  differ- 
ence between  the  action  of  an  inorganic  positive  catalyzer  and  that 
of  a  ferment;  there  is  no  distinction  in  dynamics  between  the  so-called 
formed  and  unformed  ferments.  Cells  induce  fermentations  only 
through  the  agency  of  chemical  substances  elaborated  by  them.  Fer- 
mentations tend  to  obey  the  laws  of  chemical  kinetics;  the  experimental 
deviations  are  due  to  the  multiplicity  of  adventitious  variables  and  to 
difficulties  in  the  definition  of  the  units  of  measurement.  The  greater 
the  control  in  the  experiment,  the  closer  the  approximation  to  the 
theoretical  law. 

The  experimental  study  of  a  fermentation  may  be  formulated  in 
specific  terms  as  follows : 

The  primary  reaction. 

The  relation  of  mass  of  substrate  to  reaction  velocity. 

The  relation  of  mass  of  ferment  to  reaction  velocity. 

The  relation  of  temperature  to  reaction  velocity;  temperature  opti- 
mum. 

The  reversion  of  reaction  by  ferment  action. 

The  relation  of  ferment  to  the  products  of  reaction. 

Auto-acceleration;  zy mo-excitors ;  zymo-depressors. 

The  inactivation  of  ferment. 

Secondary  reactions. 

The  nature  of  ferment;  colloidal  properties;  relation  of  activity  to 
history  and  method  of  preparation. 

The  control  of  the  conditions — the  purity  of  the  reacting  components 
and  of  the  ferment,  the  temperature,  the  concentrations,  and  the 
absence  of  inhibition  or  inactivation  of  the  ferment — will  determine 


56  THE  THEORY  OF  FERMENT  ACTION 

the  reliability  of  the  results.  It  is  to  be  confessed  that  too  often  such 
control  has  not  been  attained.  The  more  closely  the  conditions  of  the 
experiment  approximate  the  conditions  of  an  ideal  chemical  experi- 
ment, the  more  credible  the  results.  To  be  entirely  definite  the  results 
should  be  quantitative  and  capable  of  a  mathematical  interpretation. 
The  problems  of  fermentations  differ  only  in  degree  from  the  problems 
of  catalytic  reactions,  directly  in  proportion  to  our  inability  to  study 
all  the  aspects  as  above  stated,  to  control  the  variables  and  to  define 
the  units  of  measurement.  These  conditions  have  most  often  been 
best  attained  in  connection  with  the  investigations  of  ferments  derived 
from  plants  or  lower  orders  of  animal  life. 

The  statement  that  fermentations  are  to  be  regarded  as  accelera- 
tions of  existing  reactions  demands  a  certain  restriction.  The  earlier 
chemists  regarded  catalytic  reactions  as  reactions  de  novo;  the  present 
general  currency  of  the  opposite  opinion  is  due  largely  to  the  influence 
of  modern  physical  chemistry.  We  are  now  in  possession  of  a  large 
amount  of  experimental  data  confirmatory  of  this  view.  An  apparent 
objection  to  the  conception  of  fermentations  as  accelerated  reactions 
is  contained  in  the  fact  that  a  single  substance  will  yield  different 
products  under  the  influence  of  different  ferments.  The  fact  is,  how- 
ever, capable  of  another  interpretation,  one  harmonious  to  the  theory, 
that  the  product  represents  a  stage  in  the  reaction,  and  that  different 
ferments  accelerate  to  different  stages.  Secondary  and  superimposed 
reactions  are  also  to  be  considered.  In  special  instances  the  addition 
of  a  positive  catalyzer  to  a  system  in  a  state  of  chemical  rest  appears 
to  inaugurate  a  reaction ;  and  it  is  possible  that  this  may  be  of  not  such 
infrequent  occurrence  in  the  domain  of  organic  substances.  For  all 
the  known  fermentations  occurring  in  nature,  however,  it  is  clear  that 
fermentations  represent  accelerations  of  existing  reactions.  These 
auto-reactions  progress  as  a  rule  at  ordinary  temperature  with  extreme 
slowness.  In  many  instances,  however,  they  have  been  studied  and 
measured.  This  is  true  particularly  for  the  aut-oxidations  occurring 
in  metals  and  the  auto-hydrolyses  noted  in  solutions  of  organic  sub- 
stances. We  possess  likewise  accurate  studies  upon  such  reactions 
between  gases.  Indeed,  studies  upon  the  slow  reaction  between  gaseous 
oxygen  and  hydrogen  to  form  water  at  ordinary  temperature  were 
among  the  earliest  investigations  tending  to  indicate  that  catalyses 
are  accelerated  reactions  and  not  reactions  de  novo. 


CHEMICAL   REACTIONS    OF    FERMENTATIONS 

Fermentations  are  best  studied  and  classified  on  the  basis  of  the 
reactions  involved.  For  every  chemical  phenomenon  one  may  inquire: 
What  is  the  reaction?  And  also:  How  and  under  what  conditions 
does  the  reaction  proceed  ?  There  are  excellent  illustrations  of  physico- 
chemical  studies  of  chemical  processes  of  which  the  reactions  are  entirely 


CHEMICAL  REACTIONS  OF  FERMENTATIONS  57 

unknown.  The  measurement  of  the  relations  between  specific  bio- 
logical bodies  and  their  antibodies  is  an  illustration  in  point.  For  the 
enzymes,  however,  we  possess  actually  more  information  upon  the 
chemical  nature  of  the  reactions  than  upon  the  laws  under  which  they 
proceed.  The  study  of  a  fermentation  ought  to  be  carried  out  from 
the  double  point  of  view  of  organic  and  physical  chemistry ;  the  neglect 
of  the  latter  by  the  organic  chemist  and  the  narrow  formal  treatment 
of  the  problem  by  the  physical  chemist  have  deterred  the  advance  of 
knowledge. 

The  most  simple  reactions  of  catalysis  are  the  intramolecular  re- 
arrangements. Many  such  instances  are  met  with  in  organic  sub- 
stances. Aldehyd  on  standing  passes  into  the  paraldehyd.  The 
transformation  proceeds  more  rapidly  at  higher  temperature,  and  is 
especially  accelerated  by  the  presence  of  acids.     Thus  for  acetaldehyd: 


CH3CHO  +CH3CHO  +CH3CHO     <  =  >     CH3 


The  polymerization  into  paraldehyd  may  be  regarded  as  due  to 
the  conversion  of  the  aldehyd 

CH3CH  =  0  into  CH3CH 

following  which  three  such  groups  join  in  a  ring  structure  to  form  a 
saturated  substance.  The  modus  of  action  of  the  hydrogen  ions  in 
the  acceleration  of  the  polymerization  is  not  known.  The  reaction 
is  reversible,  and  tends  to  an  equilibrium. 

A  very  illustrative  reaction  of  this  type  is  the  reversible  formation 
of  dianthracin  from  anthracin.  This  is  a  photo-chemical  reaction, 
and  tends  to  an  equilibrium.  The  reaction  of  light  is  reversed  in  the 
dark,  and  thus  the  reaction  is  to  be  written 

light 

darkness 

In  all  probability  such  photo-chemical  reactions  are  numerous.  It  is 
possible  that  the  formation  of  ozone  from  atmospheric  oxygen  is  such 
a  process. 

Acetone  slowly  undergoes  polymerization  into  di-acetone  alcohol. 
The  transformation  is  much  accelerated  by  alkalies. 

2  CH3CO .  CH3     <  =  >     (CH3CO.CH3)2 

OH 

CH3CO .  CH3+CH3CO .  CH3     <  =  >     (CH3)2C CH2CO .  CH3 

The  reaction  is  reversible. 


58  THE  THEORY  OF  FERMENT  ACTION 

An  excellent  illustration  for  the  aromatic  series  is  afforded  by  the 
transformation  of  diazo-amino-benzol  into  p-amino-azo-benzol.  Acids 
accelerate. 


C6H5N:N.NH.C6H6     <  = 

=  >     C6H6N:N.C6H4.NH2 

CH 
HC      CH 
HC      CH 

Y 

CH 
HC      CH 
HC      CH 

Y 

i 

NH 

i 

ii 

1 

N 

II 
N 

A 

HC      CH 
HC      CH 

Yh 

A 

HC      CH 
HC      CH 

Y 
.   i 

NH2 

An  exceedingly  pretty  illustration  of  a  catalytic  intramolecular 
re-arrangement  is  seen  in  the  isomeric  ketons  CeClsO. 

CI  C CC12  CI  C==CC1 

II         I  II 

C1C        CC12    <  =  >     C12C        CC12 

\Y  \/ 

CO  CO 

The  reaction  is  reversible,  and  no  matter  from  which  keton  one 
proceeds  an  equilibrium  will  be  established  in  the  system.  Though 
the  sole  difference  lies  in  the  positions  of  the  double  chlorins,  the 
two  isomers  present  melting  points  as  different  as  31°  and  92°. 

Natural  fermentations  of  this  type  are  not  yet  known. 

In  the  next  group  of  catalyses  one  substance  is  broken  into  two  or 
more  molecules,  or  for  the  reversed  reaction  two  or  more  molecules 
combine  to  form  one  substance.  Some  of  these  reactions  are  of  the 
simplest  of  association  and  dissociation.    Such  are: 

Hydrogen  +  oxygen  <  =  >  water 

2  H2  +  02  <  =  >  2  H20 

* 

Hydrogen  +  iodin  <  =  >  hydriodic  acid 
H2  +  I2  <  =  >  2  HI 

Sulphur  dioxid  +  oxygen  <  =  >  sulphur  trioxid 
2S02  +  02  <  =>  2S03 


CHEMICAL  REACTIONS  OF  FERMENTATIONS  59 

These  are  all  greatly  influenced  by  changes  in  temperature,  are 
typically  reversible,  and  are  markedly  accelerated  by  the  members 
of  the  platinum  group.     Another  good  illustration  is  the  following: 

Dibrom-succinic  acid  <  =  >  bromo-malic  acid  +  hydrobromic  acid 
COOH.CHBr.CHBr.COOH  <  =>  COOH.CBr.CH.COOH.  +  HBr 

Many  fermentations  are  of  this  order. 

d-glucose  <  =  >  ethyl  alcohol  +  carbon  dioxid 
CH2OH.(CHOH)4COH  <  =  >  2CH3CH2(OH)  +  2C02 

Malic  acid  <  =  >  lactic  acid  +  carbon  dioxid 
COOH.CH2CH(OH).COOH  <  =  >  CH3.CH(OH).COOH  +  C02 

The  acceleration  of  the  reaction  in  the  case  of  d-glucose  may  be 
accomplished  by  alkali  or  platinum,  furnishing  a  good  illustration  of  the 
identical  natures  of  catalytic  and  fermentative  acceleration.  Glucose 
is  subject  to  other  fermentations. 

glucose  <  =  >  two  molecules  of  lactic  acid 

CH2OH.  (CHOH)4  COH  <  =  >  2  CH3.CH(OH)  .COOH 

This  reaction  is  an  intermediary  stage  in  the  fermentation  of  glucose 
to  ethyl  alcohol. 

d-glucose  <  =  >  butyric  acid  +  2  carbon  dioxid  +  hydrogen 
CH2OH.  (CHOH)4  COH  <  =  >  CH3CH2CH2COOH  +  2  C02  +  H2 

The  fermentation  of  sinigrin  by  myrosin  is  possibly  the  most  com- 
plicated of  the  known  reactions  of  this  group. 

Sinigrin  <  =  >  allyl-sulphocyanid  +  d-glucose  +  acid  pot.  sulphate 
C10H12NKS2O10  <  =  >  C3H5SCN  +  C6  H1206  +  KHS04 

Especially  noteworthy  is  the  formation  of  an  inorganic  electrolyte 
as  one  of  the  products. 

Most  of  the  ordinary  fermentations  involve  four  or  more  component 
molecules.  The  substrate  combines  with  another  molecule,  and  then 
divides  to  form  two  or  more  molecules.  That  our  point  of  view  begins 
with  the  body  to  be  fermented  is  simply  a  result  of  historical  develop- 
ment and  of  common  experience  with  the  phenomenon.  Dynamically 
the  two  processes  in  the  equation  are  of  the  same  dignity.  We  use 
the  term  substrate  to  indicate  the  substance  that  in  the  ordinary  sense 
of  the  term  is  the  main  component  in  the  reaction — the  substance  to 
be  fermented.  The  term  product  is  applied  to  the  substances  that 
result  from  the  reaction.  Dynamically,  what  would  be  the  products 
of  the  reaction  in  the  one  direction  are  the  primary  substances  with 
the  reaction  in  the  other  direction.    Similarly,  the  second  body  in  the 


60  THE  THEORY  OF  FERMENT  ACTION 

ordinarily  primary  reaction,  the  substance  that  is  added  to  the  sub- 
strate, is  not  in  common  usage  accorded  the  same  dignity  given  to  the 
substrate;  but  dynamically  it  is  upon  the  same  plane.  For  example: 
Ester  +  water  =  alcohol  +  fatty  acid.  The  latter  are  the  products. 
But  if  we  mix  the  alcohol  and  fatty  acid,  ester  will  be  formed,  and 
under  such  circumstances  the  ester  is  the  product.  Now,  since  both 
reactions  are  always  taking  place  side  by  side  in  the  system,  the  use 
of  the  terms  substrate  and  products  is  simply  a  matter  of  convenience, 
based  upon  the  fact  that  experiments  at  direct  fermentation  are  common, 
while  experiments  as  reversion  are  rare.  The  water,  of  course,  is  as 
essential  a  component  in  the  reaction  as  the  ester,  and  in  the  reversed 
reaction  the  water  is  as  truly  a  product.  Of  these  fermentations  there 
are  three  large  groups:    Hydrolyses,  oxidations,  and  reductions. 

Hydrolytic  Cleavage. — In  these  reactions  water  is  added,  and  the 
product  of  the  union  is  divided  into  two  or  more  molecules  of  one 
substance  or  into  two  or  more  substances.  In  the  reversions  of  these 
cleavage  reactions,  two  or  more  molecules  combine  to  form  a  larger 
molecule,  with  the  extrusion  of  water.  Hydrolytic  cleavage  seems  to 
be  universal  in  the  world  of  organic  substances;  whenever  these  sub- 
stances are  dissolved  in  water,  slow  hydrolytic  cleavages  are  inaugurated. 
These  auto-hydrolyses  have  been  demonstrated  in  a  large  number  of 
instances.  The  thermodynamic  demonstration  of  the  nature  of  the 
phenomenon  is  contained  in  the  fact  that  steam  is  a  universal  hydro- 
lysing  agent  for  these  substances,  and  since  the  reaction  occurs  rapidly 
at  high  temperature  it  must  occur  to  some  extent  at  low  temperatures. 
The  agent  in  the  auto-hydrolysis  may  be  confidently  assumed  to  be 
the  hydrogen  or  hydroxyl  ion  of  the  dissociated  water.  A  further  proof 
of  the  occurrence  of  these  auto-hydrolyses  is  contained  in  the  fact  that 
hydrogen  ions  are  general  accelerators  of  these  reactions  with  these 
substances.  In  a  certain  number  of  these  reactions,  reversions  have 
been  demonstrated,  both  by  catalytic  and  enzymic  agents;  and  the 
occurrence  of  such  reversions  under  appropriate  conditions  is  postulated 
for  all. 

Of  these  hydrolyses  many  illustrations  may  be  given.    Thus: 

Cellulose  +  water  <  =  >  hexose  -f  hexose 
n(C6H10O5)n  +  n  H20  <  =  >  n  C6H12C6  +  n  C6H1206 

The  hexose  is  d-glucose.  The  common  bacterial  fermentation  of 
cellulose  yields  no  sugar  among  the  end  products,  but  only  gases  and 
acetic  and  butyric  acid,  carbon  dioxid  being  evolved  in  all  cases  but 
otherwise  either  hydrogen  or  methane.  For  starch  and  inulin  similar 
relations  hold. 

n(C6H10O6)n  +  n  H20  <  =  >  n  C6H1206 

For  starch  the  product  is  d-glucose  when  acids  are  employed  as  the 
catalyzer,  maltose  when  diastatic  ferment  is  employed;  from  inulin 


CHEMICAL  REACTIONS  OF  FERMENTATIONS  61 

only  levulose  is  secured.  In  the  acid  hydrolysis  of  starch  the  process 
passes  through  the  stage  of  maltose  and  ends  with  the  formation  of 
the  hexose;  in  the  diastatic  fermentation  the  process  stops  at  the  stage 
of  the  disaccharid.  In  all  these  hydrolyses  of  polysaccharids  the 
reactions  pass  through  many  substages.  The  same  reaction  is  noted 
for  glycogen. 

The  disaccharids  undergo  similar  cleavages.  These  follow  the 
general  type: 

Disaccharid  +  water  <  =  >  hexose  +  hexose 
Ci2H220n  +  H20  <  =  >  C6H1206  +  C£H1206 
• 
In  the  case  of  saccharose  the  products  are  d-glucose  and  d-levulose; 
maltose  yields  d-glucose;  milk  sugar  yields  d-galactose  and  d-glucose. 
These  reactions  appear  to  occur  directly,  in  the  ordinary  sense  of  the 
term. 

Closely  related  to  the  splitting  of  the  disaccharids  are  the  hydro- 
lytic  cleavages  of  the  glucosids.  Glucosids  are  ether-like  combina- 
tions of  a  hexose  with  an  aromatic  substance,  as  an  alcohol  or  an  alde- 
hyd,  instead  of  with  another  hexose  as  in  the  case  of  a  disaccharid. 

Helicin  +  water  <  =  >  salicylic  aldehyd  +  d-glucose 
C13H1607  +  H20  <  =  >  OH.C6H4.CHO  +  C6H1206 

There  is  a  wide  range  of  variety  in  the  second  components  of  these 
compounds.  Thus  arbutin  yields  hydroquinon;  phloridzin,  phloretin; 
tannin,  gallic  acid;  gaultherin,  methylsalicylic  acid;  while  amygdalin 
yields,  in  addition  to  d-glucose,  hydrocyanic  acid  and  benzoic  aldehyd. 

For  many  of  these  hydrolyses  of  poly-  and  disaccharids,  auto- 
hydrolysis  has  been  demonstrated  directly.  To  all  of  these  reactions 
hydrogen  ions  act  as  positive  catalyzers.  For  some  of  them  the  colloidal 
metals  of  the  platinum  group  have  been  shown  to  act  as  accelerators. 
Ferments  of  the  cytase  type  accelerate  the  hydrolysis  of  cellulose; 
ferments  of  the  diastase  type  act  positively  for  the  group  of  poly- 
saccharids; enzymes  of  the  type  of  invertase  accelerate  the  cleavage 
of  the  disaccharifls  and  glucosids.  It  is  a  noteworthy  fact  that 
fermentation  of  polysaccharid,  disaccharid,  and  glucosid  is  an  act 
of  hydrolysis,  that  of  primary  sugars  is  an  intramolecular  cleavage. 
There  are  possibly  exceptions  to  this;  thus  there  is  presumed  to  be 
a  direct  fermentation  of  lactose  into  lactic  acid.  But,  as  a  rule,  the 
fermentation  of  the  higher  sugars  is  a  hydrolytic  cleavage,  while  the 
fermentation  of  the  primary  sugars  is  a  direct  intramolecular  cleavage. 
Hydroxyl  ions  are  prominent  as  catalyzers  of  the  reactions  of  the 
primary  sugars,  hydrogen  ions  conspicuous  as  catalyzer  for  the  hy- 
drolysis of  the  poly-  and  disaccharids. 

The  cleavages  of  protein  are  all  hydrolyses.     The  general  reaction 

runs: 

Protein  +  water  <  =  >  amino-acids  +  amino-acids 


62  THE  THEORY  OF  FERMENT  ACTION 

There  are  many  substages  in  the  process.  The  end  products  comprise 
a  large  number  of  different  amino-acids.  These  hydrolyses  are  also 
accelerated  by  hydrogen  ions,  and  to  some  extent  by  colloidal  platinum. 
The  auto-hydrolysis  has  been  experimentally  demonstrated  for  several 
members  of  the  protein  group.  Cleavage  with  steam  was  indeed  one 
of  the  oldest  methods  employed  for  obtaining  products  of  protein 
hydrolysis. 

The  fermentation  of  fat  is  likewise  an  instance  of  hydrolytic  cleavage. 
All  esters,  both  the  synthetic  esters  and  the  natural  fats,  are  hydro- 
lyzed  according  to  the  general  equations: 

Ethyl  acetate  +  water  <  =  >  ethyl  alcohol  +  acetic  acid 
CH3CO.O.CH3.CH2  +  H20  <  =  >  CH3.CH2.OH  +  CH3COOH 

Olein  triglycerid  +  water  <  =  >  oleic  acid  +  glycerol 
C3H6(C18H3302)3  +  3  H20  <  =  >  3  d8H3402  +  CH2(OH)  .CH(OH)  .CH2(OH) 

These  reactions  are  typically  and  measurably  reversible.  The  simple 
reactions  are  greatly  accelerated  by  hydrogen  ions,  and  to  some  extent 
by  the  colloidal  metals  of  the  platinum  group.  In  many  respects  esters 
present  the  best  opportunities  for  the  study  of  enzyme  action. 

It  is  thus  seen  that  the  fermentation  of  the  members  of  the  three 
great  groups  of  foods — protein,  carbohydrate,  and  fat — are  instances 
of  the  enzymic  acceleration  of  hydrolytic  cleavages.  These  hydrolyses 
are,  under  the  conditions  in  which  they  occur  in  nature  as  well  as  under 
the  circumstances  of  experiments,  monomolecular  reactions,  at  least 
in  so  far  as  the  reaction  in  the  direction  of  the  right  (the  hydrolysis 
of  the  substrate)  is  concerned.  The  water  of  solution  is  so  much  greater 
than  the  water  of  combination  that  the  mass  of  the  water  in  the  system 
is  for  practical  purposes  constant  during  the  duration  of  the  reaction. 

Other  interesting  instances  of  fermentative  hydrolyses  may  be 
described. 

Hippuric  acid  +  water  <  =  >  glycocoll  +  benzoic  acid 
C6H6.CO.NH.CH2.COOH  +  H20  <  =  >  CH2NH2.COOH  +  C6H5.COOH 

Urea  +  water  <  =  >  ammonia  +  carbon  dioxid 
CO(NH2)2  +  H20  <  =  >  2  NH3  +  C02 

Arginin  +  water  <  =  >  urea  +  ornithin 
NH2C.(NH)2.(CH2)3.CH.NH2.COOH  +  H20  <  =  >  CO(NH2)2  + 
CH2(NH2).(CH2)2  CH(NH2).COOH 

The  last  two  fermentations  are  accomplished  by  ferments  contained 
in  the  liver.  The  cleavages  may  be  accomplished  as  readily  by  the 
action  of  acids  as  by  ferments.  Interesting  are  the  fermentations  of 
the  salts  of  vegetable  acids.  An  illustration  is  afforded  by  calcium 
formate. 


CHEMICAL  REACTIONS  OF  FERMENTATIONS  63 

Calcium  formate  +  water  <  =  >  calcium  carbonate  +  carbon  dioxid  +  hydrogen 
HCOOv 

>Ca  +  H20  =  CaC03  +  C02  +  2  H2 
HCOCK 

The  hydrogen  acts  as  an  anticatalyzer. 

Catalytic  accelerations  of  hydrolyses  are  exceedingly  common,  not 
only  in  natural  substances,  but  also  in  synthetic  substances. 
Thus: 

Mon-chlor-acetic  acid  +  water  <  =  >  glycollic  acid  +  hydrochloric  acid 
CH2.Cl.COOH  +  H20  <  =  >  CH2.OH.COOH.  +  HC1 

Oxidation  Fermentations.— Under  oxidation  fermentations  we  under- 
stand such  accelerations  in  oxidation  as  occur  under  the  influence  of 
the  presence  of  an  enzyme.  The  steps  in  these  oxidations  are  not 
well  understood.  It  is  not  even  known  that  oxygen  is  always  added 
in  these  reactions,  since  oxidation  can  be  effected  by  the  withdrawal 
of  hydrogen  as  well  as  by  the  addition  of  oxygen.  Biologists  have  been 
inclined  to  group  the  fermentative  oxidations  under  two  headings, 
direct  and  indirect,  according  to  whether  hydrogen  peroxid  acted 
as  a  carrier  or  not.  The  data  are  not  sufficient  to  justify  such  a  dis- 
tinction. We  ought  not  to  dogmatize  upon  the  nature  of  these  reac- 
tions, since  we  are  well  acquainted  with  so  few.  When  the  knowledge 
of  the  aut-oxidation  of  inorganic  substances  now  being  accumulated 
is  applied  to  the  study  of  these  fermentations,  we  may  expect  light 
to  break  upon  the  subject.  The  best  known  instances  divide  them- 
selves in  two  groups:  Those  in  which  a  substance  combines  with 
oxygen  to  form  a  single  product,  and  those  in  which  water  is  split 
off.    Obviously  the  reversion  of  the  latter  would  constitute  hydrolyses. 

Salicylic  aldehyd  +  oxygen  <  =  >  salicylic  acid 
2  0H.C6H4CHO  +  02  <  =>  2  0H.C6H4.COOH 

CH  CH 


HC        C.CHO  HC       C.COOH 

II  -  II 

HC        C.OH  HC        C.OH 

\/  \/ 

CH  CH 

A  soluble  enzyme  of  mammalian  tissues  accelerates  this  reaction. 

Hydroquinon  +  oxygen  <  =  >  quinon  +  water 
20H.C6H4.OH  +  02  <  =>  2CO.C4H4.CO  +2H20 

C.OH  CO 

/\  /\ 

HC   CH  HC   CH 


HG   CH 


HC   CH 


C.OH  CO 


64  THE   THEORY  OF  FERMENT  ACTION 

This  fermentation,  which  is  induced  by  the  juice  of  the  Japanese 
lac  tree  (laccase),  and  also  by  mammalian  intestinal  secretions,  com- 
prises, according  to  the  modern  conception  of  these  substances,  the 
transformation  of  a  true  aromatic  substance  into  an  alicyclic  substance. 

A  good  illustration  is  furnished  by  the  acetic  acid  fermentation  of 
ethyl  alcohol,  occurring  in  two  stages. 

Ethyl  alcohol  +  oxygen  <  =  >  acetaldehyd  +  water 
2  CH3CH2.OH  +  02  <  =  >  2  CH3.COH  +  2  H20 

Acetaldehyd  +  oxygen  <  =  >  acetic  acid 
2  CH3.COH  +  02  <  =  >  2  CH3.COOH 

Oxidation  ferments  are  very  active  in  the  purin  catabolism.  One 
illustration  will  suffice.  Xanthinoxydase  converts  hypoxanthin  first 
into  xanthin,  then  into  uric  acid. 

Hypoxanthin  Xanthin  Uric  acid 

HN— CO  HN— CO  HN— CO 

HC    C— NH.  ->  OC     C— NHV  -*  OC     C— NHX 

!l     II  >CH  I      II  >CH  I      ||  >CO 

N— C— N  *  HN— C— N   *  HN— C— NPK 

Two  interesting  fermentations  are  brought  about  by  the  Bac.  xylinum. 

Sorbite  +  oxygen  <  =  >  sorbose  +  water 
2  C6H1406  +  02  <  =  >  2  C6H1206  +  2  H20 

Glycerol  +  oxygen  <  =  >  di-oxy-acetone  +  water 
2  CH2(OH) .  CH(OH) .  CH2(OH)  +  02  <  =  >  2  CH2(OH) .  CO .  CH2(OH)  +  2  H20 

These  reactions  have  not  been  reversed.  For  all  of  them  inorganic 
accelerators  are  known. 

While  inorganic  accelerators  of  the  oxidation  of  the  inorganic  salts 
of  metals  are  numerous,  fermentative  acceleration  of  such  oxidations 
are  known  certainly  to  exist  only  for  the  nitrites.    The  reaction: 

Metal  -  N02  +  O  <  =  >  Metal  -  N03 

is  a  reversible  reaction  that  is  going  on  constantly  in  soils  and  waters 
under  the  influence  of  bacteria,  certain  microorganisms  being  especially 
active  in  the  one  or  the  other  direction.  Whether  in  the  reduction 
hydrogen  is  added  and  then  water  extruded  is  not  known;  indeed,  the 
mechanisms  of  the  reactions  have  not  been  determined  on  account  of 
the  complexity  of  the  conditions  under  which  the  phenomena  occur. 
The  oxidation  of  nitrite  to  nitrate  has  long  been  known  to  agriculture; 
the  reduction  of  nitrate  to  nitrite  has  been  learned  more  recently. 
Analogous  fermentations  have  been  described  for  the  salts  of  sulphur. 
Closely  related  to  simple  oxidations  are  the  reactions  with  hydrogen 
peroxid.      Hydrogen  peroxid    tends    to  a    slow    reduction,   and    the 


CHEMICAL  REACTIONS  OF  FERMENTATIONS  65 

oxidations  of  substances  by  hydrogen  peroxid  are  in  general  to  be 
regarded  as  accelerations  of  this  auto-reduction. 

Hydriodic  acid  +  hydrogen  peroxid  <  =  >  iodin  +  water 
2  HI  +  H202  <  =  >  I2  +  2  H20 

Sulphurous  acid  +  hydrogen  peroxid  =  sulphuric  acid  +  "water 
H2S03  +  H202  <  =  >  H2S04  +  H20 

The  oxidation  of  formic  aldehyd  occurs  in  two  stages. 

Formaldehyd  +  hydrogen  peroxid  <  =  >  formic  acid  +  water 
H.COH  +  H202  <  =  >  H.COOH  +  H20 

Formic  acid  +  hydrogen  peroxid  <  =  >  carbon  dioxid  +  water 
H.COOH  +  H202  <  =  >  C02  +  2  H20 

There  is  evidence  tending  to  indicate  that  the  reversion  of  these 
reactions  represents  the  initial  steps  whereby  carbohydrates  are  formed 
by  plants,  though  the  reactions  are  usually  written  with  oxygen  alone: 

C02  +  H20  =  H.COOH  +  O  and  H.COOH  =  H.COH  +  O 

The  theory  assumes  the  presence  in  the  chlorophyl-containing  cell 
of  some  enzyme  accelerating  the  reductions,  subject  to  the  influence 
of  light.  Since  carbon  dioxid  and  water  are  universally  present  in 
the  atmosphere,  one  has  but  to  assume  the  removal  or  combination 
of  the  formaldehyd  (i.  e.,  its  condensation  into  sugar)  in  order  to 
possess  a  firm  physico-chemical  basis  for  the  continued  reaction  of 
reduction.  The  influence  of  light  may  possibly  be  interpreted  to  lie 
in  a  translocation  of  the  station  of  equilibrium  in  the  direction  of  the 
reaction  of  reduction.  Investigations  indicate  that  in  the  reduction 
of  carbon  dioxid  to  formic  acid  carbon  monoxid  may  be  formed, 
and  that  both  ozone  and  hydrogen  peroxid  appear. 

2  C02  <  =  >  2  CO  +  02 
CO  +  H20  <  =  >  H.COOH 

3  02  <  =  >  203 

03  +  H20  <  =  >  H202  +  02 
C02  +  H202  <  =  >  H.CHO  +  03 

Formaldehyd  would  be  thus  derived  in  one  or  both  of  two  ways. 
From  formaldehyd  sugar  would  be  formed  by  condensation.  The 
steps  in  the  earlier  stages  of  the  condensation  of  formaldehyd  are 
not  known;  it  is  only  certain  that  amino-acids  are  not  concerned. 
This  general  conception  has  been  given  a  certain  experimental  founda- 
tion by  investigations  on  the  effects  of  the  silent  electrical  discharge 
in  a  system  containing  carbon  dioxid  and  water;  reduction  products 
were  obtained  that  conform  quite  closely  to  the  above  scheme.  Though 
a  goodly  amount  of  experimental  work  lies  at  the  basis  of  these  theories, 
5 


66  THE  THEORY  OF  FERMENT  ACTION 

it  is  apparent  that  the  analytical  demonstrations  of  traces  of  hydrogen 
peroxid  and  formaldehyd,  appearing  as  transient  stages  in  a  reaction, 
must  be  a  hazardous  test.  Nevertheless,  it  has  been  experimentally 
shown  that  chlorophyl  in  the  presence  of  sunlight  builds  formaldehyd 
from  carbon  dioxid  and  water.  A  further  biological  difficulty  lies  in  the 
great  toxicity  of  formaldehyd,  though  this  is  obviated  by  the  assump- 
tion of  immediate  combination  or  elaboration  into  higher  carbohydrates. 

The  reactions  of  hydrogen  peroxid  are  susceptible  of  acceleration 
by  a  large  number  of  inorganic  substances,  especially  by  ferrous  salts, 
colloidal  metals  of  the  platinum  group,  molybdic  and  tungstic  acids. 
The  acceleration  of  the  reactions  of  formaldehyd  and  formic  acid  may 
be  accomplished  with  plant  extracts. 

Fermentative  Reductions. — Fermentative  reductions,  the  acceleration 
of  reactions  of  reduction,  have  not  been  long  known.  Indeed,  the 
existence  of  such  fermentations  was  once  denied.  Curiously  enough, 
our  present  knowledge  includes  few  instances  of  the  fermentative 
acceleration  of  reductions  of  organic  substances,  most  of  the  recognized 
reactions  concerning  metallic  salts.  The  reduction  of  the  nitrate  to 
the  nitrite  mentioned  in  a  previous  paragraph  is  probably  the  most 
widely  occurring  reaction  of  the  type  known.  This  fermentation  occurs 
also  in  mammalian  juices.  Very  interesting  are  the  reductions  of  the 
acids  and  salts  of  selenium  and  tellurium  by  certain  bacteria.  These 
reductions  follow  the  regular  types : 

Selenous  acid  +  sulphurous  acid  <  =  >  sulphuric  acid  +  selenium  +  water 
H2Se03  +  2  H2S03  <  =  >  2  H2S04  +  Se  +  H20 

Tellurous  acid  +  sulphurous  acid  <  =  >  sulphuric  acid  +  tellurium  +  water 
H2Te03  +  2  H2S03  <  =  >  2  H2S04  +  Te  +  H20 

We  do  not  know  what  the  reducing  body  actually  is  that  reacts  with 
the  selenous  and  tellurous  acids  (replacing  the  sulphurous  acid  in  the 
written  reactions)  in  these  bacterial  experiments,  but  the  acceleration 
is  very  pronounced,  and  is  observed  with  the  -ous  and  -ic  acids  and 
their  salts  alike.  In  some  instances  the  reduction  may  only  be  to  a 
lower  oxide.  Similar  reactions  occur  with  arsenic,  both  in  the  arsenous 
and  arsenic  states. 

Arsenic  trioxid  +  hydrogen  <  =  >  arsenuretted  hydrogen  +  oxygen 
2  As03  +  3  H2  <  =  >  2  AsH3  +  3  02 

Arsenic  trioxid  +  potassium  acetate  <  =  >  cacodylic  oxid  +  pot.  carbonate  + 
carbon  dioxid 
As203  +  4KC2H302  <  =  >  (As(CH3)2)20  +  2K2C03  +  2C02 

These  accelerations  are  produced  in  the  culture  media  of  certain 

bacteria;  the  steps  and  details  in  the  reactions  are  not  worked  out. 

Of  the  fermentative  reductions  of  organic  substances  we  will  cite  two: 


CHEMICAL  REACTIONS  OF  FERMENTATIONS  67 


Nitrobenzol  +  hydrogen  <  =  ; 

>  anilin  +  water 

C6H5.N02  +  3H2 

<  =  >  C6H, 

,  NH2  +  2H20 

N02 

NH2 

A 

A 

/\ 

/\ 

HC        CH 

HC        CH 

1          1 
HC       CH 

<  =  > 

HC       CH 

\/ 

v 

CH 

CH 

This  reduction  is  accelerated  by  some  substance  contained  in  extracts 
of  mammalian  tissues  and  in  extract  of  yeast.  What  the  actual  reduc- 
ing component  in  the  reaction  is  we  do  not  know;  it  is  certainly  not 
hydrogen  itself. 

Aspartic  acid  +  hydrogen  <  =  >  ammonium  succinate 
COOH .  CH  (NH2) .  CH2 .  COOH  +  H2  <  =  >  COOH .  CH2 .  CH2 .  COOH .  NH3 

This  reduction  is  accomplished  by  many  of  the  common  bacteria, 
such  as  the  Bacillus  coli  communis.  The  component  substance  that 
reacts  with  the  amino-succinic  acid  is  not  known. 

Other  fermentations  are  known  that  do  not  fit  naturally  into  any 
of  these  groups.  An  illustration  may  be  given  in  the  deaminization 
ferments — substances  that  accelerate  the  replacement  of  the  amino 
group  by  an  hydroxyl  group  in  the  various  amino-acids  that  are  prod- 
ucts of  the  hydrolysis  of  protein,  and  also  the  replacement  of  the 
amino  group  in  guanin  and  adenin  by  hydrogen.  Thus  the  action 
of  guanase  may  be  illustrated  as  follows : 


Guanin  +  H20  =  xanthin  +  NH3 

HN— CO  HN— CO 

H2N.C    C-NHX  OC     C— NH 

II      II  >CH        -  ||     || 

N— C— N    '  HN— C— N 


The  deaminization  of  amino-acids  are  enzymic  reactions  of  great 
importance.    This  process  may  be  illustrated  for  alanin: 

CH3  CH3 

CH.NH2  +  H20  =  CHOH  +  NH3 

COOH 


a 


The  amino-propionic  acid  is  converted  into  lactic  acid.  This  reaction 
directly  viewed  is,  of  course,  an  hydrolysis.  But  it  is  also  an  oxida- 
tion, since  the  oxy-acid  is  formed. 

The  formation  of  acetone  from  aceto-acetic  acid  gives  an  illustration 
of  another  unusual  reaction. 


68  THE  THEORY  OF  FERMENT  ACTION 


Aceto-acetic  acid  Acetone 

CH3  CH3 

I  I 

CO         =  CO 


i 


I 

H2  CH3 

COOH  C02 


Similar  reactions  by  splitting  off  of  carbon  dioxid  are  the  formation 
of  taurin  from  cysteinic  acid  and  the  derivation  of  p-oxy-phenyl- 
ethyl-amin  from  tyrosin.  It  is  clear  that  some  hydrolyses  constitute 
what  especially  from  the  physiological  standpoint  must  be  interpreted 
as  oxidations;  the  splitting  off  of  carbon  dioxid  is  really  a  reduction. 

General  Features. — These  illustrations  will  suffice  to  afford  a  general 
view  of  the  final  relations  determined  by  the  reactions  of  fermentation 
of  different  types.  For  nearly  all  these  accelerated  reactions  the  slow 
auto-reactions  are  known.  For  many  of  these  processes  reversions 
have  been  accomplished.  For  many  of  these  reactions  the  influence 
of  variation  in  temperature  is  known.  These  facts  afford  a  natural 
presumption  that  the  reactions  of  catalysis  and  fermentation  are  essen- 
tially identical. 

In  looking  over  these  reactions  one  cannot  fail  to  be  impressed 
with  certain  general  features.  The  heat  relations  in  fermentations 
vary.  In  the  common  hydrolyses  the  products  have  approximately 
the  same  heat  value  as  the  substrate.  The  oxidations,  on  the  con- 
trary, are  exothermic,  the  reductions  endothermic  reactions.  Natural 
fermentations  convert  complex  substances  into  simple  substances, 
they  convert  colloids  into  electrolytes,  electrolytes  into  simple  gases 
and  elements.  Most  of  the  substances  that  are  commonly  the  sub- 
strates of  fermentations  are  but  slightly  soluble  in  water,  or  even 
incapable  of  true  solution  but  only  of  a  colloidal  suspension.  Starches, 
cellulose,  proteins,  glucosids,  fats,  all  form  in  water  more  or  less  col- 
loidal suspensions  and  many  display  further  the  tendency  to  form  hydro- 
gels.  When  these  substances  are  fermented,  the  products  are  substances 
of  greater  solubility,  quite  devoid  of  colloidal  characteristics,  with  no 
tendency  to  the  formation  of  hydrogels.  Through  the  fermentation 
the  system  has  been,  converted  from  the  heterogeneous  to  the  homo- 
geneous state.  The  substrates  of  natural  fermentations  are  usually 
substances  of  very  large  molecular  weight;  the  products  possess  small 
molecular  weight.  These  substrates  are  almost  devoid  of  the  power 
of  diffusion,  the  products  diffuse  readily  as  a  rule.  The  natural  sub- 
strates exert  little  depression  of  the  freezing  point  of  their  solutions, 
the  products  exert  usually  a  marked  depression;  the  substrates  possess 
little  osmotic  pressure,  the  products  marked  osmotic  pressure.  The 
substrates  are  rarely  crystalloidal,  the  products  are  usually  crystal- 
loidal.  The  substrates  are  substances  that  are  not  subject  to  elec- 
trolytic dissociation;  the  products  often  exhibit  this  property.  The 
substrates  are  substances  with  little  tendency  to  chemical  reaction  as 


CHEMICAL  REACTIONS  OF  FERMENTATIONS  69 

compared  to  the  products.  There  are,  of  course,  exceptions  to  these 
statements;  for  instance,  the  properties  of  the  higher  fatty  acids  are 
in  these  respects  but  little  different  from  their  fats.  The  natural  fer- 
mentations usually  comprise  the  disintegration  of  complex  substances 
that  have  been  synthesized  in  the  vegetable  or  animal  organism.  Since 
all  fermentations  are  to  be  regarded  as  reversible  processes,  how  obvious 
and  attractive  is  the  suggestion  that  the  natural  fermentations  are 
simply  the  reversion  of  the  reactions  whereby  these  substances  were 
formed.  There  are  no  thermodynamic  reasons  that  plead  against  this 
proposition.  The  fact  that  fermentations  of  the  natural  order  are 
exothermic  reactions  has  been  employed  by  some  biologists  in  support 
of  a  teleological  interpretation  of  the  circumstances,  according  to 
which  a  synthesis  could  not  be  held  to  be  accomplished  by  the  action 
of  a  ferment.  As  will  be  pointed  out,  this  interpretation  is  lacking  in 
theoretical  validity. 

It  must  be  conceded  that  the  pendulum  may  swing  too  far  and  that 
fermentations  may  be  accorded  a  too  general  scope  in  physiological 
and  pathological  processes.  The  theoretical  possibility  for  such  an  over- 
generalization  lies  in  the  very  definition  of  fermentation.  We  have 
defined  fermentation  as  the  acceleration  of  some  existing  reaction  by 
a  substance  formed  in  a  plant  or  animal  organism.  When  we  reflect, 
further,  that  theoretically  every  reaction  is  capable  of  acceleration, 
the  boundless  application  of  the  principle  becomes  apparent.  It  is, 
however,  clear  that  chemical  biology  is  in  no  greater  danger  of  becom- 
ing simply  a  treatise  on  fermentations  than  are  inorganic  and  organic 
chemistry  in  danger  of  becoming  reduced  to  a  treatise  on  catalysis, 
since  the  same  principles  apply  to  all.  In  each  individual  instance 
the  question  whether  a  particular  phenomenon  may  be  a  fermenta- 
tion (or  a  catalysis)  is  plainly  a  matter  of  concrete  demonstration. 
And  it  is  because  this  concrete  demonstration  must  be  so  much  more 
difficult  in  biological  than  in  chemical  questions,  that  there  will  be 
a  tendency  among  biologists  to  overwork  the  principle.  Standing 
bewildered  before  the  apparently  hopeless  complexity  of  a  biological 
problem,  it  is  so  easy  to  say  "ferment  action."  This  very  tendency 
compels  us  to  insist  with  the  greatest  objective  strictness  upon  the 
precise  demonstration  of  the  occurrence  of  a  fermentation.  The  safety 
of  the  investigator  lies  in  close  adherence  to  the  laws  of  general  chemistry 
connected  with  the  kinetics  of  reactions.  Not  only  do  these  serve  as 
controls  in  our  studies,  they  enable  us  to  investigate  in  a  proper  and 
adequate  manner  the  characteristics  of  a  fermentation,  once  its  identity 
as  such  has  been  established.  The  importance  of  the  study  of  fermenta- 
tions has  been  entirely  underestimated  by  the  biological  world.  While 
in  the  groupings  of  systematic  biology  it  may  have  sufficed  to  know 
simply  that  a  particular  phenomenon  was  a  fermentation,  for  the 
real  study  of  the  chemistry  of  the  functions  of  animals  and  plants, 
that  is  simply  the  stating  of  the  problem.     The  height  of  biological 


70  THE  THEORY  OF  FERMENT  ACTION 

research  is  the  reproduction  of  an  act  of  nature.  To  attempt  to  repro- 
duce the  chemical  functions  of  organized  bodies,  one  must  study  fer- 
mentation from  the  point  of  view  of  the  control  of  its  several  variables. 

APPLICATION  OF  LAWS  OF  CATALYSIS  TO  FERMENTATIONS 

We  define  a  catalysis  as  an  acceleration  of  an  already  existing  reac- 
tion through  the  presence  of  another  body  that  does  not  appear  in  the 
end  products  of  the  reaction.  In  the  specific  instance  there  are  two 
criteria  of  catalysis.  Every  alteration  in  velocity  not  dependent  upon 
alteration  in  concentration  or  of  temperature  indicates  catalysis; 
and  in  the  catalytic  acceleration  there  are  no  stoichiometric  relations 
between  the  catalyzer  and  substrate  or  products.  There  is  theo- 
retically a  catalyzer  for  every  reaction,  and  every  substance  may  act 
as  a  catalyzer.  Certain  classes  of  bodies  possess  to  a  high  degree  this 
quality  of  acceleration :  The  platinum  group,  colloidal  metals,  hydrogen, 
and  hydroxyl  ions,  and  the  oxids  and  oxyhydrates  of  the  elements  of 
varying  valency,  such  as  iron,  manganese,  and  nitrogen.  The  rela- 
tions of  energy  involved  in  a  reaction  are  not  disturbed  by  catalytic 
acceleration;  the  result  is  achieved  by  a  diminution  of  the  chemical 
resistance.  The  existence  of  a  large  class  of  compounds  in  the  natural 
state  is  dependent  absolutely  upon  their  chemical  resistance,  and  were 
this  materially  diminished,  these  compounds  would  cease  to  exist. 
Chemical  resistance  diminishes  with  increasing  temperature,  and 
there  is  an  optimal  temperature  for  each  concentration  of  a  chemical 
system.  Corresponding  to  the  physical  state  of  the  system,  we  dis- 
tinguish between  catalyses  in  homogeneous  and  in  heterogeneous 
systems.  The  current  theory  of  physical  states  is  that  from  the  homo- 
geneous to  the  heterogeneous  state  is  a  gradual  transition.  In  fermenta- 
tions we  deal  with  bodies  that  present  with  water  less  of  homogeneity 
than  solutions  of  pure  crystalloids,  and  usually  less  of  heterogeneity 
than  the  typical  suspension  colloids.  We  shall  see  that  the  behavior 
of  fermentations  confirms  this  interpretation. 

In  our  consideration  of  the  kinetics  of  catalysis  we  are  concerned 
in  the  first  instance  with  the  law  of  mass  action,  and  especially  as  applied 
to  a  reaction  of  which  the  products  may  reunite  to  form  the  original 
substance  to  a  measurable  degree;  and,  secondly,  with  the  relations 
observed  when  such  a  reaction  is  accelerated  by  the  presence  of  a  posi- 
tive catalyzer  or  enzyme.  Theoretically  all  reactions  are  to  be  looked 
upon  as  limited  reactions  and  likewise  reversible;  but  the  point  of 
equilibrium  may  be  so  slightly  removed  from  the  condition  of  a  com- 
plete reaction  as  not  to  be  analytically  determinable;  and  it  is  not 
always  possible  to  fix  the  conditions  favorable  to  a  reversion  so  that 
the  theoretical  result  shall  become  experimentally  apparent.  What 
is  about  to  be  enunciated  under  these  headings  is  specifically  valid 
only  for  homogeneous  systems;  the  relations  involved  when  hetero- 
geneous systems  are  concerned  will  be  considered  later. 


APPLICATION  OF  LAWS  OF  CATALYSIS  TO  FERMENTATIONS     71 

The  fundamental  proposition  concerned  in  the  kinetics  of  chemical 
reaction  is  that  under  constant  conditions  of  experimentation  the 
transformation  in  the  unit  of  time  is  proportional  to  the  mass  of  the 
reacting  bodies.  This  proposition  is  directly  analogous  to  the  law  for 
radiation  of  heat  from  a  warm  to  a  cold  body;  the  radiation  in  time  is 
proportional  to  the  difference  in  temperature  between  the  two  bodies. 
The  formulation  may  be  expressed  in  another  way  in  the  statement 
that  whenever  a  transformation  is  taking  place,  the  rapidity  of  that 
transformation  in  a  particular  moment  is  proportional  to  the  distance 
between  the  end  point  (the  equilibrium)  and  the  point  in  the  course 
of  the  reaction  attained  at  that  particular  moment.  Applied  to  the 
concrete  instance,  say  to  the  inversion  of  cane  sugar,  we  mean  that 
in  each  particular  moment  the  amount  of  sugar  inverted  is  proportional 
to  the  amount  of  uninverted  sugar  present  in  that  same  moment.  This 
applies  as  stated  only  to  monomolecular  reactions — reactions  in  which 
the  mass  of  only  one  substance  is  affected  during  the  reaction.  But 
the  general  proposition  applies  to  bimolecular  and  trimolecular  reac- 
tions, with  the  difference  that  the  degree  of  reaction  in  time  depends 
upon  the  concentration  of  the  two  or  three  active  masses,  instead  of 
depending  simply  upon  one.  Now  all  the  fermentations  occurring  in 
the  biological  world  are  monomolecular  reactions,  because  the  second 
body  concerned,  as  water  or  oxygen,  is  present  in  such  excess  that 
alteration  in  its  mass  is  of  almost  no  consequence.  If,  for  instance, 
in  the  reaction  cane  sugar  +  water  =  glucose  +  fructose  the  amount 
of  water  present  was  approximate  to  the  amount  required  in  the  reac- 
tion, that  reaction  would  be  treated  as  a  bimolecular  reaction;  but 
as  the  experiment  is  carried  out  in  dilute  solution,  where  the  water, 
as  solvent,  is  present  in  a  thousand  times  the  amount  required  for  the 
water  as  reagent,  the  reaction  is  equivalent  to  a  monomolecular  reac- 
tion. For  this  reason  we  will  confine  ourselves  to  the  kinetics  of  the 
monomolecular  reaction: 

d  Conctr. 

=  Const.  Conctr. 

dt 

This  proposition  is  expressed  in  the  differential  equation: 

dx 

—  =  C  (A  —  x) 
dt 

A  is  the  original  amount  of  substrate,  x  the  amount  of  substance  con- 
verted in  the  time  t,  C  is  a  constant.  -The  equation  holds  only  when 
the  temperature  and  volume  are  held  constant,  and  the  system  is  in  a 
state  of  certain  dilution.  When  integrated  and  reduced  to  its  simplest 
relations  under  the  stipulation  that  when  t  =  O,  x  also  =  O,  the  equa- 
tion becomes: 

1            A 
C  =  —  log 

t         A  — x 


72  THE  THEORY  OF  FERMENT  ACTION 

In  practice  the  equation  is  often  used  in  a  modified  form,  though 
directly  derived  from  the  one  stated: 

1  A  — Xl 

C  = log 

t2 — ti         A  —  x2 

This  often  gives  a  better  concordance,  as  the  first  estimations  are  likely 
to  be  irregular.  The  constant  expresses  the  work  done  under  constant 
conditions.  If,  for  example,  we  determine  with  a  particular  strength 
of  acid  in  an  inversion  experiment  that  C  =  0.002,  that  means  that 
under  constant  conditions  of  temperature,  volume,  and  concentration 
of  acid,  in  a  solution  of  sugar  of  the  strength  of  a  gram  molecule  in 
the  liter,  0.002  gram  molecule  of  sugar  will  be  inverted  in  the  first 
minute,  and  if  we  could  add  to  the  system  in  each  minute  without 
changing  the  volume  0.002  gram  molecule  of  sugar,  that  quantity 
would  be  inverted  regularly  each  minute. 

This  simple  relation  becomes  more  complicated  when  we  deal  with  a 
reaction  of  active  and  measurable  reversibility.  Under  these  circum- 
stances an  equilibrium  is  established  in  the  system  when  the  opposing 
reactions  just  compensate  each  other.  The  reaction  in  the  direction  of 
the  right  becomes  less  each  minute  as  the  mass  of  substrate  becomes 
less;  the  reaction  in  the  direction  of  the  left  becomes  greater  each 
moment  as  the  mass  of  the  products  of  the  other  reaction  increases.  At 
a  certain  point  these  will  be  equal,  and  from  this  time  no  apparent 
change  will  be  observable  in  the  system.  But  it  must  not  be  supposed 
that  the  reactions  have  stopped;  they  continue  as  before  proportional 
to  the  active  masses  of  the  respective  components,  but  since  they  are 
balanced,  the  system  is  in  equilibrium. 

The  reaction  may  be  written  in  the  following  manner,  using  as  an 
illustration  the  reaction  ester  +  water  =  alcohol  +  fatty  acid. 

Ester  +  water  <  =  >  alcohol  +  fatty  acid 

ester  water  alcohol     fatty  acid 

Const.  Concentrn.       .     Concentrn.  =  Const.  Concentrn.  Concentrn. 

— >  < — 

alcohol.  fatty  acid 

Concentrn.  .     Concentrn.  Const.  — » 

= =  Const. 

ester.  water        Const.  <— 

Concentrn.         .      Concentrn. 
Const,  stands  for  the  constant  of  equilibrium 

When  a  catalyzer  is  added  to  such  a  system  under  conditions  of 
controlled  relations  in  experiments  with  pure  substances,  nothing 
happens  except  that  the  time  of  the  reactions  is  shortened.  The 
accelerated  reaction  that  naturally  was  practically  a  complete  reaction 
remains  practically  a  complete  reaction;  it  is  simply  completed  more 
quickly;  and  with  different  quantities  of  catalyzer  the  differences  are 


APPLICATION  OF  LAWS  OF  CATALYSIS  TO  FERMENTATIONS     73 

simply  those  of  degrees  of  rapidity.  The  accelerated  reaction  of  measur- 
able reversibility  remains  a  reaction  of  reversibility  and  the  point  of 
equilibrium  is  not  disturbed  by  the  acceleration;  the 


is  simply  reached  more  quickly.  As  stated,  however,  the  conditions 
must  be  controlled.  Concentration  and  volume  must  be  held  constant, 
in  order  that  the  relations  of  the  active  mass  or  masses  are  maintained; 
the  temperature  must  be  held  constant  because  the  point  of  equilibrium 
will  vary  with  the  temperature;  and  the  products  must  not  combine 
with  the  catalyzer,  for  in  this  manner  also  would  the  constant  of  equilib- 
rium be  disturbed.  It  is  also  very  important  that  pure  substances 
be  employed,  since  traces  of  foreign  bodies  may  exert  a  very  great 
disturbance. 

Let  us  now  examine  the  conditions  and  variations  somewhat  in 
detail. 

Initial  Concentration  of  the  Substrate. — This  is  not  immaterial,  and 
it  is  not  true  that  at  all  concentrations  of  the  substrate  the  reaction 
in  any  particular  moment  is  proportional  to  the  active  mass  of  the 
substrate.  This  statement  is  true  sometimes  only  of  dilute  solutions, 
just  as  the  laws  of  electrolytic  dissociation  hold  true  only  for  dilute 
solutions.  If  one  endeavors,  in  accordance  with  the  current  tendency, 
to  rest  catalytic  reactions  upon  the  theory  of  ionization,  this  fact 
becomes  in  a  general  sense  intelligible.  A  further  bearing  upon  the 
disturbing  action  of  high  concentrations  of  the  substrate  lies  in  the 
fact  that  under  such  circumstances  the  substrate  participates  in  the 
role  of  solvent;  the  vapor  pressure  of  the  catalyzer  may  be  thereby 
altered,  since  under  such  circumstances  the  solvent  will  be  modified. 
Not  only  is  the  velocity  of  a  reaction  dependent  upon  a  proper  dilution 
of  the  substrate;  the  order  of  a  reaction  is  likewise  altered  by  excessive 
concentration.  In  a  monomolecular  reaction,  under  conditions  of 
proper  concentration,  when  the  system  is  diluted  the  times  of  equal 
proportional  transformation  are  not  altered;  doubling  the  concen- 
tration doubles  the  velocity.  Under  similar  circumstances  with  a 
bimolecular  reaction,  when  the  system  is  diluted  the  times  of  equal 
proportional  transformation  are  inversely  as  the  initial  concentrations; 
doubling  the  concentrations  quadruples  the  reaction  velocity.  Now 
under  conditions  of  high  concentration  these  relations  do  not  hold, 
and  it  is  thus  necessary  to  provide  for  proper  dilution  when  determin- 
ing the  order  of  a  reaction  as  well  as  when  determining  the  velocity. 
The  necessity  of  high  dilution  of  the  substrate  is  most  urgent  in  the 
case  of  substrates  of  ponderous  molecular  weight. 

Concentration  of  the  Products.— This  is  likewise  not  immaterial.  In 
general,  the  higher  concentrations  of  the  products,  the  more  energetic 
the  process  of  reversion.     But  in  experimental  catalysis  it  is  some- 


74  THE  THEORY  OF  FERMENT  ACTION 

times  found  that  when  the  concentration  of  the  system  is  high  the 
resultant  high  concentration  of  the  products  disturbs  the  course  of 
the  reaction. 

Influence  of  Temperature. — The  acceleration  of  reaction  velocities 
by  increase  in  temperature  holds  good  for  catalytic  reactions  as  well 
as  for  simple  ones.  For  such  work  the  simple  formula  of  Arrhenius 
will  usually  suffice: 


ki  /Tj  —  TA 

ln-  =  A    

k2  \  Tx.T,  / 


A  being  the  constant  and  ki  and  k2  the  velocity  constants  of  the  reac- 
tion at  the  absolute  temperatures  Ti  and  T2.  The  equation  has  been 
tested  on  many  catalytic  reactions.  Corresponding  very  closely  in 
its  results  to  the  above  equation  is  the  empirical  rule  of  van't  Hoff 
that  for  every  10°  increase  in  temperature  the  velocity  of  a  reaction  is 
doubled,  i.  e.,  the  time  required  to  do  a  unit  of  transformation  is 
reduced  one-half, 

V  at  Tn  +  io 

=  2  + 

VatTn 

For  ferments  the  rule  holds  good  in  a  restricted  sense.  The  rule  holds 
for  most  ferments  from  about  15°  to  35°;  above  this  the  increase  in 
velocity  is  often  much  more  than  predicated  by  the  rule,  while  above 
45°  there  is  a  rapid  fall  to  zero.  The  fall  is  the  result  of  the  destruction 
of  the  ferment,  a  condition  not  contemplated  in  the  rule.  As  a  whole, 
however,  in  consideration  of  the  complexities  attending  the  experi- 
mentation, the  concordance  of  the  facts  with  the  theory  is  quite  good. 

It  is  a  common  error  to  suppose  that  a  temperature  optimum  is 
peculiar  to  ferment  action.  Every  reaction  has  a  temperature  optimum, 
and  this  optimum  is  usually  altered  (lowered)  in  a  catalytic  accelera- 
tion. The  system  S02  +  O  =  S03  has  its  temperature  optimum  about 
900°;  at  1000°  the  system  is  in  equilibrium,  the  velocity  of  the  reactions 
being,  however,  very  slow.  In  the  presence  of  platinum  the  tempera- 
ture optimum  is  lowered  to  about  450°,  the  velocity  is  rapid,  and  as 
the  reversed  reaction  (the  dissociation  of  S03)  does  not  occur  to  any 
material  extent  below  500°,  the  acceleration  of  the  reaction  is  very 
effective.  The  catalytic  acceleration  of  the  formation  of  water  from 
oxygen  and  hydrogen  also  displays  a  sharp  optimum.  Ferments  are 
notable  simply  for  the  lowness  of  the  temperature  optimum,  and  for 
the  narrowness  of  the  optimal  range.  The  latter  condition  has  lost 
much  of  its  significance,  since  we  have  learned  that  the  sharp  descent 
of  the  curve  from  the  optimal  temperature  is  due  in  large  part  to  the 
destruction  of  the  ferment. 

Relations  of  the  Catalyzer. — The  typical  positive  catalyzer  simply 
accelerates  the  velocity  of  a  reaction  without  altering  the  nature  of 


APPLICATION  OF  LAWS  OF  CATALYSIS  TO  FERMENTATIONS     75 

the  reaction,  the  order  of  the  reaction,  the  character  or  yield  of  the 
products,  the  point  of  equilibrium,  and  without  being  itself  altered  in 
the  process.  It  is  just  as  though  there  were  a  certain  resistance  to  the 
progress  of  the  reaction,  and  the  presence  of  the  catalyzer  diminished 
this  resistance,  like  a  lubrication.  These  conditions  are  often  but  not 
always  maintained  in  inorganic  catalyses,  afe  as  a  rule  not  fully  main- 
tained in  the  acceleration  of  reactions  involving  organic  substances, 
while  they  may  be  said  to  be  rarely  realized  in  fermentations.  Since 
the  presence  of  the  catalyzer  simply  accelerates  the  reaction,  it  ought 
in  general  to  do  so  proportionally  to  the  quantity  of  the  catalyzer 
employed,  and  this  is  usually  true.  Especially  for  the  catalytic  action 
of  hydrogen  ions  has  this  relationship  been  shown  to  be  true;  the  cata- 
lytic action  of  acids  is  related  to  their  electrolytic  dissociation.  The 
same  holds  true  for  hydroxyl  ions.  For  other  catalyzers  the  same  rule 
has  in  general  been  found  to  hold  good.  There  are,  however,  several 
well-studied  reactions,  for  which  the  catalytic  acceleration  is  not  pro- 
portional to  the  quantity  of  catalyzer.  Thus,  in  the  reaction  between 
stannous  chloride  and  ferric  chloride  the  catalytic  acceleration  of  acids 
is  proportional  to  the  square  of  the  hydrogen  ions;  and  in  the  catalytic 
reduction  of  hydrogen  peroxide  by  colloidal  platinum  the  acceleration 
is  not  proportional  to  the  quantity  of  platinum. 

The  relation  of  the  mass  of  ferment  to  the  acceleration  of  the  reac- 
tion may  be  usually  expressed  in  the  equation  of  Bredig: 


i  _  /FAi 

2  \F2/ 


The  C  is  the  constant  of  velocity  for  the  ferment  concentration  of  F, 
m  is  constant.  For  the  common  catalyzers  m  =  1  and  this  holds  for 
many  ferments.  The  proportionality  holds  for  low  concentrations 
only. 

To  the  statement  that  the  order  of  a  reaction  is  not  altered  by  the 
presence  of  a  positive  catalyzer,  exceptions  seem  to  exist.  The  reac- 
tion H202  +  2  HI  =  2  H20  +  I2  depends  upon  the  concentration  of 
the  two  reacting  bodies;  that  is,  it  is  a  bimolecular  reaction.  Under 
the  influence  of  molybdic  acid  and  iron  sulphate,  the  velocity  of  the 
reaction  is  a  function  of  the  concentration  of  hydrogen  peroxid,  that 
is,  the  presence  of  the  catalyzer  had  converted  the  reaction  from  one 
of  the  second  to  a  reaction  of  the  first  order.  There  exist  also  other 
studies  suggesting  a  similar  shifting  in  the  order  of  the  reaction,  though 
in  none  have  the  relations  been  so  carefully  worked  out.  The  altera- 
tion is  unquestionably  to  be  explained  upon  the  basis  of  intermediary 
reactions. 

The  statement  that  the  station  of  equilibrium  is  not  translocated 
by  the  presence  of  a  catalyzer  seems  to  hold  absolutely  good  unless 
the  catalyzer  is  altered  in  the  progress  of  the  reaction,  and  there  is 
for  this  statement  experimental  evidence  as  well  as  thermodynamic 


76  THE  THEORY  OF  FERMENT  ACTION 

theory.  The  acceleration  of  the  catalyzer  per  se  simply  multiplies 
the  V  and "?  of  the  equation,  the  C  is  not  affected  by  the  acceleration. 
When,  however,  the  catalyzer  is  altered  during  the  course  of  the  reac- 
tion, it  means  that  the  substrate,  the  products  or  the  solvent  has  entered 
into  reaction  with  the  catalyzer,  as  a  consequence  the  concentration  of 
one  or  other  member  of  the  system  has  been  altered,  and  as  a  result 
of  this  the  station  of  equilibrium  has  been  shifted. 

The  remarks  previously  made  upon  the  necessity  of  adequate  dilu- 
tion hold  also  for  the  catalyzer.  When  to  a  system  is  added  an  excess 
of  a  catalyzer,  bizarre  and  irregular  results  may  be  expected.  For 
such  catalyzers  as  act  through  ionization  this  behavior  is  quite  intelli- 
gible. It  is  here  again  possible  that  at  a  high  concentration  of  the 
catalyzer  it  will  in  part  participate  in  the  solution  of  the  substrate. 
Under  such  circumstances  the  solvent  is  not  identical  with  that  in  a 
system  at  high  dilution,  and  since  the  station  of  equilibrium  may  be 
shifted  very  materially  by  alterations  in  the  solvent,  irregular  results 
might  be  expected  for  this  reason  alone.  Furthermore,  the  active  mass 
of  the  substrate  cannot  be  assumed  to  be  the  same  in  the  changed 
state  of  the  solvent.  There  is  in  any  event  no  necessity  for  the  use 
of  high  concentrations  of  the  catalyzer,  since  one  of  the  most  striking 
aspects  of  these  accelerations  is  the  minimal  amount  of  catalyzer 
required  to  effect  a  notable  acceleration. 

Inactivation. — Under  the  term  in  activation  are  understood  several 
different  relations.  The  slowing  of  the  reaction  under  the  influence  of 
concentration  of  the  products  is  a  manifestation  of  the  mass  law,  and 
ought  not  to  be  referred  to  as  an  inactivation  of  the  ferment.  The 
ferment  may  be  inactivated  by  union  with  some  extraneous  body, 
or  even  by  its  mere  presence;  in  a  purely  chemical  inactivation  the 
ferment  will  be  restored  to  power  when  the  offending  condition  is 
removed.  Lastly,  the  ferment  may  be  inactivated  by  hydrolysis  or 
oxidation,  in  which  it  is  destroyed  as  a  catalytic  agent. 

Under  certain  conditions  the  presence  of  a  substance  not  itself  a 
catalyzer  will  enhance  the  acceleration  of  a  known  catalyzer.  A  good 
illustration  of  this  fact  is  contained  in  the  observation  that  the  presence 
of  a  trace  of  cupric  sulphate,  in  itself  inactive,  will  increase  enormously 
the  acceleration  of  the  reduction  of  hydrogen  peroxid  by  ferrous  sulphate. 
The  mechanism  of  such  zymo-excitation  is  unclear. 

As  there  are  accelerating  substances,  so  there  are  retarding  sub- 
stances. We  must  here  distinguish  between  negative  catalyzers  and 
anticatalyzers.  A  negative  catalyzer  would  be  a  substance  that  retards 
the  auto-reaction.  Anticatalyzers  are  substances  that  inhibit  in  part 
the  accelerating  action  of  a  positive  catalyzer.  Without  denying  that 
genuine  negative  catalyzers  exist,  it  is  certain  that  the  bodies  described 
as  such  have  been  anticatalyzers.  In  many  inorganic  reactions  the 
most  trifling  amounts  of  foreign  substances  may  act  as  pronounced  anti- 
catalyzers, and  there  can  be  no  doubt  that  in  the  domain  of  ferments 
such  influences  are  still  more  numerous  and  potent. 


APPLICATION  OF  LAWS  OF  CATALYSIS  TO  FERMENTATIONS     77 

Station  of  Equilibrium. — The  station  of  equilibrium  in  a  reaction  of 
reversible  character  is  dependent  upon  certain  conditions.  In  the 
ideal  sense  it  applies  to  a  system  at  constant  temperature  in  a  high 
and  constant  dilution.  It  is  possible  experimentally  to  alter  the  station 
of  equilibrium  in  several  ways.  More  of  the  substrate  may  be  added, 
in  which  event  the  reaction  in  the  direction  of  the  right  will  again  assume 
the  leadership  until  a  new  balance  is  established.  Some  of  the  sub- 
strate may  be  removed,  in  which  event  the  reaction  in  the  direction 
of  the  left  will  be  accelerated  until  a  new  balance  is  established.  The 
products  may  be  removed  or  more  of  those  bodies  added,  with  the 
resultant  accelerations  in  the  respective  reactions  until  new  equilibria 
are  established.  Or  only  one  of  the  products  may  be  added;  thus  one 
can  add  acetic  acid  to  the  system  ethyl  acetate  +  water  =  acetic  acid 
+  ethyl  alcohol  until  the  equilibrium  is  established  in  the  sense  that 
there  are  but  two  bodies  present,  ethyl  acetate  and  acetic  acid.  The 
station  of  equilibrium  may  also  be  altered  by  dilution  or  concentra- 
tion of  the  entire  system.  Alteration  in  temperature  may  also  bring 
with  it  an  alteration  in  the  station  of  equilibrium,  must  indeed  if  the 
reaction  be  endo-  or  exothermic.  To  these  we  must  add  two  final 
procedures  for  the  translocation  of  the  point  of  equilibrium — reactions 
between  ferments  and  components,  and  reactions  between  solvent 
and  product.  These  considerations  of  alterations  in  the  station  of 
equilibrium  are  of  great  importance  in  the  study  of  fermentations, 
and  much  of  the  reigning  confusion  has  been  due  to  neglect  of  them. 

Purity  of  the  Reacting  Bodies. — This  is  generally  of  great  importance 
for  the  regular  progression  of  catalytic  accelerations.  The  simple 
presence  of  foreign  bodies  is  not  itself  of  necessity  a  disturbing  factor; 
extraneous  substances  may  be  divided  into  active  and  inactive.  A 
trace  of  an  active  substance  may  seriously  disturb  the  reaction  in  an 
otherwise  flawless  catalysis;  a  good  illustration  is  afforded  in  the  inhibi- 
tion that  may  be  exerted  upon  a  large  mass  of  platinum  by  a  trace  of 
arsenic  in  the  contact  method  for  the  manufacture  of  sulphuric  acid. 
On  the  other  hand,  the  mere  presence  of  one  or  a  number  of  inert  sub- 
stances may  have  little  or  no  disturbing  effect.  We  shall  later  see 
that  it  is  sometimes  possible  to  secure  good  quantitative  results  in 
fermentation  experiments  conducted  with  materials  known  to  be  very 
complex.  In  other  instances  good  results  are  not  secured,  the  difference 
depending  not  upon  the  presence  of  foreign  substances,  but  upon  the 
presence  of  particular  foreign  substances  that  are  active  in  their  chemical 
relations  to  some  member  of  the  system  under  investigation.  In  various 
chemical  investigations  of  this  matter  it  has  been  acids,  alkalies,  and 
inorganic  salts  in  particular  that  have  produced  disturbances  in  the 
progress  of  catalytic  accelerations.  A  priori,  we  must  understand 
that  since  we  conceive  the  modus  operandi  of  catalytic  acceleration  to 
lie  in  successive  intermediary  reactions,  there  must  be  for  each  type 
or  group  of  reactions  certain  substances  whose  introduction  into  the 
system  would  lead  to  different  reactions,  that  would  proceed  more  or 


78  THE   THEORY  OF  FERMENT  ACTION 

less  at  the  expense  of,  and  certainly  to  marked  disturbance  of  the  quan- 
titative progression  in,  the  original  reaction.  Just  as  there  are  certain 
substances  and  conditions  that  prevent  a  good  yield  in  the  synthesis 
of  organic  substances,  and  these  conditions  and  substances  vary  for 
the  different  synthetic  procedures;  so  there  are  conditions  and  sub- 
stances that  disturb  or  prevent  the  regular  march  of  a  catalytic 
acceleration,  and  these  conditions  and  substances  will  vary  with  the 
different  reactions  whose  accelerations  are  being  studied. 

APPLICATION    OF    LAWS    OF    REACTIONS    TO    FERMENTATIONS 

Concentration  of  the  Substrate. — This  is  in  fermentations  often  difficult 
to  adjust  and  determine.  Most  of  the  materials  that  are  employed 
as  the  substrate  of  fermentations  are  natural  substances  and,  there- 
fore, never  pure.  Furthermore,  it  is  often  not  possible  to  determine 
the  quantitative  degree  of  impurity.  Let  us  take  starch  for  illustra- 
tion. Starch  contains  a  certain  amount  of  ash,  composed  of  various 
inorganic  bodies.  It  contains  also  organic  bodies,  traces  of  sugar, 
fats,  protein,  and  what  not  more.  These  bodies  cannot  be  separated 
from-  starch,  and  the  only  way  of  determining  the  actual  amount  of 
starch  is  to  hydrolyze  completely  with  acid  and  then  determine  the 
sugar  present,  and  even  this  method  would  neglect  the  preformed 
sugars.  When,  therefore,  one  prepares  a  1  per  cent,  solution  of  starch, 
one  does  not  know  with  just  how  much  less  than  a  1  per  cent,  solution 
one  is  actually  working.  But  more,  starches  vary  in  their  resistance 
to  hydrolytic  cleavages,  depending  upon  their  origin,  mode  of  prepara- 
tion, age,  and  method  of  preservation.  A  certain  starch  might  be 
already  partially  hydrolyzed  to  as  much  as  10  per  cent.,  depending 
on  the  method  of  preparation  and  preservation.  Let  us  further  con- 
sider albumin.  All  that  has  been  said  of  native  starch  holds  true  of 
native  albumin  to  still  greater  degree.  Not  only  are  foreign  substances 
present  to  greater  extent  and  in  greater  variety  than  in  starch,  but 
the  tendency  to -alteration  in  the  albumin  itself  is  more  pronounced. 
Furthermore,  an  albumin  is  usually  composed  of  several  proteins, 
and  unless  one  works  with  a  pure  protein  like  casein  the  experiment 
actually  involves  the  digestion  of  several  proteins,  of  possibly  widely 
varying  resistance  to  hydrolysis.  While  it  is  possible  in  some  instances 
to  carry  along  in  the  same  solution  two  catalyses  of  different  materials 
and  have  each  maintain  its  own  proper  velocity  (the  inversion  of  sugar 
and  the  cleavage  of  methyl  acetate  by  acids),  it  would  not  be  possible 
to  do  so  under  circumstances  where  the  products  of  the  one  reaction 
make  the  measurement  of  the  other  reaction  uncertain  or  futile.  Yet 
this  is  what  is  attempted  when  egg  albumin  is  employed  as  substrate. 
It  is  obvious,  therefore,  that  it  is  often  not  possible  to  fix  the  concentra- 
tion of  and  to  exclude  plurality  in  the  substrate.  Now  since  the  con- 
centration of  the  active  mass  of  the  substrate  is  a  fixed  requirement, 
it  is  clear  that  at  the  very  outset  in  a  fermentation  we  are  confronted 


APPLICATION  OF  LAWS  OF  REACTIONS  TO  FERMENTATIONS     79 

with  an  inability  to  define  properly  the  conditions  of  the  experiment. 
In  the  early  part  of  the  fermentation  this  indefinite  minus  in  the  con- 
centration will  not  disturb  the  results  so  seriously,  but  toward  the 
close  of  the  reaction  the  influence  must  be  marked.  This  state  of 
affairs  is,  of  course,  not  general;  we  can  prepare  cane  sugar,  any  of  the 
hexoses,  alcohols,  and  the  synthetic  fats  with  a  high  degree  of  purity, 
and  it  has  been  along  these  lines  that  much  of  the  best  work  has  been 
done.  One  ought  always  to  attempt  the  purification  of  materials;  but 
very  often  such  attempts  at  purification  only  lead  to  some  denaturation 
of  the  substance,  so  that  nothing  is  gained. 

Experience  with  fermentations  teaches  that  there  are  three  zones 
of  concentration  with  particular  behaviors.  In  the  zone  of  high  con- 
centrations, variations  lead  to  no  changes  in  velocity.  In  a  system 
with  an  excessive  concentration  of  substrate,  the  velocity  depends  on 
the  concentration  of  ferment  alone;  within  certain  limits,  variations 
in  the  substrate  have  no  result.  Where  both  substrate  and  ferment 
are  in  excessive  concentration,  irregular  and  bizarre  results  will  be 
obtained.  In  the  zone  of  medium  concentrations,  the  velocity  of  the 
transformation  is  a  function  of  the  mass  of  substrate,  and  the  intensity 
of  the  acceleration  is  a  function  of  the  concentration  of  ferment,  but 
there  is  an  interdependence.  The  intensity  of  the  fermentative  accelera- 
tion accomplished  by  a  constant  concentration  of  ferment  will  vary  to 
some  extent  with  the  concentration  of  the  substrate.  For  different 
concentrations  of  substrate  the  ferment  seems  to  set  a  different  pace, 
a  condition  that  suggests  a  sort  of  a  stoicheiometric  relation.  Most  of 
the  experiments  with  ferments  have  been  conducted  within  this  zone 
of  concentrations.  In  the  last  zone  of  concentration,  that  of  high  dilu- 
tions, the  velocity  of  the  transformation  is  the  function  of  the  sub- 
strate concentration,  the  intensity  of  the  acceleration  is  the  function 
of  the  mass  of  ferment  and  these  are  independent,  just  as  they  should 
be  in  a  pure  catalysis.  When  operating  within  this  zone,  dilution  of 
the  entire  system  (in  monomolecular  reaction)  has  no  effect  upon  the 
proportionalities  of  the  reaction,  while  the  contrary  is  observed  on 
dilution  of  the  system  in  the  other  zones  of  concentration.  If  the 
proper  conditions  can  be  attained,  this  zone  will  be  found  in  most 
fermentations.  It  has  been  demonstrated  for  invertase,  lactase,  maltase, 
trypsin,  erepsin,  lipase,  and  catalase.  For  the  study  of  fermentation 
from  the  kinetic  point  of  view,  this  zone  of  concentration  is  obviously 
the  one  to  be  sought. 

It  must  be  insisted  upon  that  the  failure  of  the  law  of  mass  action 
to  hold  within  wide  limits  of  concentrations  is  not  peculiar  to  the 
phenomena  of  fermentations.  For  many  of  our  best  known  physico- 
chemical  laws  the  conformity  of  fact  to  theory  is  confined  to  narrow 
limits  of  conditions.  The  general  equation  for  simple  bimolecular 
reactions :  j^^  !5>**^w 

dd  \ 
=  kdCu 


80  THE   THEORY  OF  FERMENT  ACTION 

is  valid  only  for  very  high  dilutions,  practically  tenth  normal.  The 
law  of  electrolytic  dissociation  applies  only  to  conditions  of  high  or 
theoretically  infinite  dilution,  and  the  variations  that  are  induced  in 
the  system  by  the  presence  of  undissociated  molecules  are  well  known. 
Similar  relations  are  naturally  to  be  expected  in  fermentations,  and  the 
multiplicity  of  the  conditions  should  lead  us  to  expect  the  relations  here 
to  be  still  much  more  complex. 

Measurement  of  the  Reaction. — Frequently  we  are  not  in  a  position 
to  measure  in  an  accurate  analytical  manner  the  products  of  the  reaction . 
It  is  rare  that  we  have  the  opportunity  to  measure  the  products  with 
a  polariscope,  by  a  direct  accurate  titration,  or  by  a  determination  of 
conductivity.  More  often  we  need  to  undertake  a  formal  isolation  of 
the  desired  product  and  then  identify  it  and  measure  it  by  means 
of  chemical  behavior.  In  some  instances  such  a  procedure  may  yield 
accurate  results,  but  it  may  not  be  feasible  to  do  this  in  the  number 
of  determinations  necessary  in  a  measurement  of  reaction  velocity. 
Sometimes  the  product  may  not  be  accurately  estimated  in  any  way, 
as  in  the  case  of  the  digestion  of  protein. 

A  more  serious  complication  arises  with  a  great  many  fermentations 
in  which  the  reaction  occupies  not  one  but  many  stages.  These  mediated 
catalyses  exceed  the  direct  catalyses  in  the  organic  world.  We  have 
substrate  +  water  =  producti  -f  product^  producti  +  water  =  p2  + 
p2,  etc. ;  and  finally  pn  +  water  =  end  product  +  end  product.  These 
really  represent  a  series  of  successive  catalyses.  The  reactions,  bow- 
ever,  do  not  progress  in  complete  stages;  that  is,  all  of  the  substrate 
is  not  first  converted  into  producti;  and  all  of  product:  then  converted 
into  product2,  and  so  on  until  the  end  products  are  reached.  On  the 
contrary,  several  of  the  products  may  be  found  in  the  mixture  in  a 
particular  moment.  Each  of  these  stages  represents  work.  Now  in 
a  fermentation  experiment  under  such  conditions,  what  shall  one  meas- 
ure? Obviously  if  one  wishes  to  measure  the  transformation  of  the 
substrate,  one  must  measure  producti,  which  cannot  be  done  because 
the  stage  is  not  completed  en  bloc.  If  one  measures  the  end  product, 
what  one  really  measures  is  the  appearance  of  the  end  product  and  not 
the  conversion  of  the  substrate.  And  yet  the  measurement  of  the  end 
product  may  be  the  only  possible  measurement.  Under  these  circum- 
stances we  employ  the  equation 

1  A 

C  = log. 


t  (A  —  x) 

so  that  under  A  we  understand  the  quantity  of  end  product  when  the 
reaction  is  completed  and  under  x  the  quantity  of  end  product  formed 
in  the  time  t.  Under  these  circumstances  it  becomes  possible  to  work 
with  fermentations  involving  reactions  in  many  stages,  though  in  some 
instances  the  results  are  very  irregular.  It  is  apparent  that  while  a 
positive  result  might  indicate  that  the  law  holds  good  for  the  particular 


APPLICATION  OF  LAWS  OF  REACTIONS  TO  FERMENTATIONS      81 

fermentation,  a  negative  result  would  not  indicate  the  converse;  it 
would  indicate  nothing,  beyond  that  the  conditions  of  experimenta- 
tion were  too  uncontrolled  to  yield  results  susceptible  of  interpretation. 
The  majority  of  the  fermentations  of  great  biological  importance  belong 
to  this  class  of  mediated  catalyses;  no  highly  organized  body  like 
cellulose,  starch,  or  protein  may  be  hydrolyzed  into  simple  crystalloid 
end  products  in  a  single  main  reaction.  It  must  be  realized  that  this 
constitutes  not  an  analytical  but  a  fundamental  difficulty.    The  equation 

dx 

-  =  C  (A  -  x) 
dt 

presupposes  that  the  substance  undergoing  transformation  exists 
in  each  moment  in  the  system  either  in  the  form  of  unaltered  substrate 
A  or  of  product  x.  The  intermediary  reactions  from  the  state  A  to  x 
are  not .  held  to  occupy  measurable  time.  If  now  the  substrate  in  the 
moment  of  analysis  exists  in  part  in  the  state  of  e,  f,  or  more  states, 
and  not  either  as  A  or  x,  the  equation  cannot  apply.  This  is  precisely 
what  occurs  in  the  digestion  of  complex  substances  like  protein  and 
starch;  and  under  these  circumstances  one  cannot  be  surprised  that 
the  fermentations  of  these  substances  do  not  follow  closely  the  law  of 
mass  action  as  expressed  in  the  equation. 

Reversion  of  the  Reaction.— The  equation  for  the  simple  monomolec- 
ular  reaction  does  not  contemplate  a  reversion  of  the  reaction.  For 
fermentations,  however,  we  postulate  theoretically  such  a  reversion. 
If  such  reversion  occurs  with  anything  like  measurable  rapidity,  the 
constants  obtained  in  series  tests  with  the  use  of  the  equation  cannot 
be  identical  and  an  entirely  different  mathematical  formulation  will 
be  necessary.  That  a  certain  degree  of  reversion  occurs  in  actual 
fermentations  has  been  practically  assumed  on  the  basis  of  three  facts: 
the  substrate  is  never  completely  fermented;  removal  of  the  products 
increases  the  completeness  of  the  fermentation  and  reinaugurates 
it  after  it  has  ceased;  and  the  reinoval  of  the  products  increases  the 
rapidity  of  the  fermentation.  It  must,  however,  not  be  overlooked 
that  two  of  these  results  could  be  due  to  chemical  influence  of  the 
products  upon  the  ferment.  As  a  matter  of  fact,  the  results  of  the  many 
known  experiments  in  reversion  by  ferment  action  (in  which  the  fer- 
ment has  been  mixed  with  the  products  of  the  reaction)  has  been  to 
indicate  that  reversions  occur  with  great  slowness  as  compared  to  the 
reaction  of  cleavage.  If  one  attempts  to  incorporate  into  the  equation 
of  a  monomolecular  reaction  as  a  conditioning  factor  that  rapidity 
of  reversion  experimentally  observed  in  direct  tests,  the  deviation  will 
be  almost  nil.  In  addition  to  this,  the  station  of  equilibrium  is  for 
most  substrates  at  high  dilution  so  near  to  a  complete  reaction  that 
reversion  could  scarcely  be  held  to  modify  to  any  appreciable  extent 
the  mathematical  expression  of  a  ferment  reaction.  Nevertheless,  the 
actual  determination  of  the  extent  of  this  variable  lies  not  in  mathe- 
6 


82  THE  THEORY  OF  FERMENT  ACTION 

matical  considerations,  but  in  the  direct  experiment.  This  may  be  one 
of  the  reasons  why  the  experimental  velocities  in  fermentations  do  not 
always  agree  with  the  mathematical  predications. 

Concentration  of  Ferment. — It  is  as  difficult  to  obtain  and  maintain 
a  constant  concentration  of  the  ferment  as  of  the  substrate.  The 
activities  of  ferments  as  well  as  their  stabilities  seem  to  depend  to  a 
marked  degree  upon  the  methods  of  preparation  and  conservation. 
All  ferments  contain  more  or  less  extraneous  matter;  probably  in  most 
instances  the  percentage  of  the  actual  ferment  is  but  a  small  fraction 
of  the  weight  of  the  preparation  employed.  Under  such  circumstances 
it  is  not  possible  to  define  the  exact  initial  concentration  of  ferment, 
and  this  results  in  an  indeterminate  error  in  the  course  of  series  of 
experiments. 

The  lack  of  regularity  between  the  chemical  composition  and  enzymic 
activity  of  a  ferment  is  a  condition  not  peculiar  to  ferments,  but  is  an 
unfortunate  quality  of  all  colloids;  for  its  designation  we  may  amplify 
the  use  of  the  term  hysterisis.  The  age,  origin,  method  of  preparation, 
in  short  every  incident  in  the  history  of  a  colloid  tends  to  influence  its 
chemical  qualities.  Further  than  this,  once  prepared  and  conserved 
under  constant  condition,  colloids  tend  slowly  to  alterations,  a 
denaturation  that  must  be  conceived  to  lead  to  a  reduction  in  the 
dynamically  active  mass  of  the  colloid. 

Of  far  greater  practical  importance  than  the  difficulty  in  determin- 
ing the  initial  concentration  is  the  impossibility  of  maintaining  the 
concentration.  Ferments  as  a  class  have  been  held  to  differ  from 
inorganic  catalyzers  in  that  the  latter  emerge  from  the  completed 
reaction  unchanged.  This  is  not  true,  for  the  colloidal  metals  are 
subject  to  similar  reductions  in  their  catalytic  properites;  in  some 
instances  the  inactivation  is  accompanied  by  precipitation  in  a 
granular  amorphous  form,  but  in  other  instances  the  appearances  of 
the  colloid  undergo  no  change.  The  inactivation  proceeds  more  rapidly 
at  high  temperatures,  and  seems  to  affect  old  suspensions  more  than 
fresh  preparations. 

All  ferments  are  more  or  less  altered  during  the  course  of  a  fermenta- 
tion. Upon  the  supposition  that  we  are  dealing  with  pure  conditions, 
there  are  apparently  three  conceivable  sources  for  these  alterations, 
namely,  reactions  with  the  substrate,  the  products,  the  solvent.  We 
have  no  knowledge  of  reactions  between  the  substrate  and  ferment 
that  would  result  in  inactivation  of  the  ferment.  There  is  a  good 
illustration  of  this  relation  in  the  acceleration  of  the  reduction  of 
hydrogen  peroxid  by  colloidal  silver;  the  substrate  combines  with  a 
portion  of  the  silver  to  form  a  compound  that  is  catalytically  inactive. 
We  have  little  chemical  knowledge  of  the  inactivation  of  ferments  by 
reactions  with  the  products.  Trypsin  is  more  rapidly  destroyed  in  a 
solution  of  amino-acids  (products  of  tryptic  digestion)  than  in  simple 
watery  solution.  Vegetable  lipase  is  somewhat  sensitive  to  acids,  and 
is  destroyed  more  rapidly  in  even  moderate  concentrations  of  acetic 


APPLICATION  OF  LAWS  OF  REACTIONS  TO  FERMENTATIONS     83 

acid  than  in  distilled  water.  Ferments,  however,  often  combine  with 
the  products  of  the  reaction.  In  all  probability,  however,  the  chief 
reaction  resulting  in  the  destruction  of  the  ferment  is  hydrolysis  upon 
the  part  of  the  solvent.  Just  as  the  albumin  or  ester  constituting  the 
substrate,  on  suspension  in  water  undergoes  a  slow  hydrolytic  cleavage 
of  which  the  digestion  is  but  the  acceleration,  so  ferments  on  suspen- 
sion in  water  undergo  hydrolysis;  and  as  the  products  are  not  active 
in  the  catalytic  sense,  the  active  concentration  of  the  ferment  is  thus 
steadily  reduced  during  the  progress  of  the  experiment.  The  two 
hydrolyses,  of  the  substrate  and  of  the  ferment,  proceed  side  by  side 
and  probably  entirely  independently.  The  hydrolysis  of  the  ferment 
is,  of  course,  accelerated  by  increase  in  temperature,  and  seems  to 
follow  the  usual  rule  for  such  increase.  The  destruction  of  vegetable 
lipase  proceeds  closely  according  to  the  rule,  while  the  destruction 
of  trypsin  proceeds  rather  more  rapidly.  The  possible  extent  of  such 
an  inactivation  will  be  understood  when  one  realizes  that  in  some 
instances  a  solution  of  trypsin  may  be  inactivated  one-fifth  in  an  hour; 
and  the  degree  of  disturbance  that  must  follow  becomes  apparent 
when  we  consider  that  some  half  dozen  hours  might  be  required  for 
a  digestion  experiment  with  such  a  solution.  In  their  resistance  to 
hydrolysis  ferments,  however,  vary  widely.  The  inactivation  of  the 
ferment  proceeds  usually  more  rapidly  in  simple  solution  in  water  than 
during  the  course  of  a  fermentation  experiment;  this  has  been  shown 
to  be  true  for  amylase,  invertase,  trypsin,  vegetable  lipase,  and  zymase. 
The  natural  interpretation  of  this  phenomenon  is  that  during  the 
course  of  the  fermentation  the  ferment  is  passing  through  intermediary 
reactions  with  the  substrate,  and  that  when  thus  combined  its  hydro- 
lysis is  suspended.  The  free  ferment  adds  water  to  undergo  cleavage; 
in  the  complex  substrate-ferment  this  reaction  does  not  occur. 

Inactivation  of  the  ferment  may  be  produced  also  by  reactions  with 
extraneous  substances.  Theoretically  it  ought  always  to  be  possible 
to  distinguish  between  inactivation  and  destruction  of  a  ferment; 
practically  this  may  not  be  always  possible.  The  phenomenon  is  very 
frequent  in  actual  experimental  work,  and  may  also  be  provoked  in 
inorganic  catalyses.  The  accelerating  action  of  iron  salts  may  be 
abolished  by  the  presence  of  acetic  or  oxalic  acid;  the  accelerating 
action  of  colloidal  platinum  is  depressed  by  hydrocyanic  acid  or  a 
thiosulphate,  as  well  as  by  alkalies,  etc.  These  influences  are  not  all 
of  one  nature;  in  some  the  ferment  or  catalyzer  is  destroyed;  in  others 
the  action  is  inhibited  though  the  substance  is  not  altered,  for  when 
the  depressing  body  is  removed  the  original  activity  of  acceleration 
returns.  Colloidal  platinum  again  affords  a  striking  illustration;  the 
inhibition  of  its  catalytic  acceleration  by  hydrocyanic  acid,  carbon 
monoxid  or  phosphorus  will  pass  away  with  the  removal  of  these 
substances  while  the  inhibition  following  the  addition  of  sulphuretted 
arsenic,  iodin,  or  mercuric  chlorid  remains  after  the  removal  of  those 
bodies.     For  the  natural  ferments  the  negatively  catalytic  influences 


M  THE  THEORY  OF  FERMENT  ACTION 

are  exceedingly  numerous,  and  in  nearly  all  instances  they  effect  a 
permanent  inaetivation.  Many  of  these  substances  act  by  acceler- 
ating the  hydrolytie  cleavage  of  the  ferment,  that  is.  they  arc  positive 
catalyzers  to  the  hydrolysis  of  the  ferment.  Such  is  almost  certainly 
the  nature  of  the  influence  of  acids  and  alkali 

The  combination  of  ferment  with  the  products  of  the  reaction  is  a 
disturbing  factor  in  many  fermentations.  The  so-called  rule  of  Schutz 
is  an  expression  of  this  disturbance;  the  enzyme  combines  with  the 
reaction  products  and  the  active  mass  of  the  ferment  is  inversely  pro- 
portional to  the  mass  of  the  reaction  products. 

Stimulation  of  the  ferment  by  the  presence  of  substances  not  in 
themselves  accelerators  is  very  frequently  observed  in  connection 
with  fermentations.  Thus  a  trace  of  acid  aids  the  action  oi  invertase, 
vegetable  lipase,  and  of  the  ferments  of  the  pepsin  group;  a  trace  of 
alkali  aids  many  reductions  and  also  the  fermentations  of  the  trypsin 
group.  Many  salts  have  similar  actions,  as  have  innumerable  other 
substances.  These  zymo-excitors  seem  to  have  two  things  in  common : 
An  optimal  concentration  and  an  optimal  temperature.  A  good  illus- 
tration of  these  facts  (and  one  that  has  the  further  value  that  it  also 
illustrates  the  identity  of  the  conditions  in  the  organic  and  inorganic 
worlds)  is  to  be  found  in  the  zymo-excitation  by  alkali  of  the  reduc- 
tion of  hydrogen  peroxid  by  colloidal  platinum  and  oxidase  of  animal 
origin;  for  both  of  these  reactions  one  may  obtain  a  curve  of  the  influ- 
ence of  increasing  alkali  content  with  a  well-defined  maximum,  and 
for  different  alkali  content  also  a  curve  of  temperature  influence  with 
a  well-defined  maximum.  Some  instances  if  zymo-depression  and 
zymo-stimulation  will  be  considered  in  detail  in  connection  with  the 
discussion  of  particular  fermentations. 

Despite  all  extraneous  factors,  working  with  a  proper  constant 
concentration  of  substrate  the  velocity  of  reaction  has  been  shown  to 
vary  proportionately  with  the  mass  of  ferment  in  the  case  of  trypsin, 
erepsin,  lactase,  invertase.  lipase,  rennin  and  hemase. 

Station  of  Equilibrium. — We  have  to  deal  here  with  a  most  interest- 
ing phase  of  the  question  of  fermentations.  Pure  positive  catalyzers 
do  not  usually  bring  about  any  translocation  oi  the  station  of  equilib- 
rium. When  such  a  thing  occurs  in  an  inorganic  catalysis  it  is  because 
some  one  of  the  possible  factors  mentioned  has  intervened.  But  in  the 
domain  of  fermentations  we  encounter  a  new  state  of  affairs,  namely, 
that  reactions  in  themselves  practically  complete  and  unlimited,  and 
which  remain  practically  complete  reactions  when  accelerated  by 
inorganic  catalyzers  like  acids,  seem  to  become  limited  reactions  when 
accelerated  by  ferments.  Many  ferments  seem  practically  unable 
to  carry  through  their  accelerations  to  the  point  oi  complete  conver- 
sion of  substrate  into  products  that  is  observed  when  inorganic  cata- 
lyzers are  employed.     This  is  not  trtie  of  all  ferments,  but  of  a  great 

many,  and  the  phenomenon  is  especially  observed  in  the  hydrolysis 
of  starch,  glucosids,  and  protein. 


REVERSION  OP  FERMENT  ACTION  85 

The  tacts  are  as  follows:  A  certain  reaction  when  accelerated  with 
hydrogen  ions  is  practically  a  complete  reaction.  Let  us  say  the 
condition  of  the  system  may  be  represented  by  the  relations  substrate 
1  :  products  99.  At  this  point  the  reactions  in  each  direction  are 
equal;  the  tendency  to  combination  upon  the  part  of  the  products  is 
very  slight  since  with  all  the  mass  of  products  the  combination  is  only 
able  to  balance  the  cleavage  of  the  substrate  when  its  mass  has  fallen 
to  1  per  cent.  When  this  same  reaction  is  accelerated  by  a  ferment  the 
cleavage  will  not  be  nearly  so  complete,  and  at  the  close  the  relations 
may  be  expressed  something  like  substrate  15  :  products  85.  Does 
this  apparent  shifting  in  the  point  of  equilibrium  correspond  to  a  real 
translocation  of  the  station  of  equilibrium,  to  a  change  in  the  constant 
of  equilibrium?  There  are  many  facts  which  tend  to  indicate  that 
such  may  really  be  the  case.  The  addition  of  more  substrate  to  the 
system  after  the  reaction  has  ceased  to  progress  will  serve  to  reinagurate 
the  reaction.  When  products  of  the  reaction  are  added  early  in  the 
course  of  the  experiment,  the  reaction  will  cease  sooner  than  other- 
wise, and  cease  sooner  proportionately  to  the  quantity  of  products 
added.  On  the  other  hand,  when  the  products  are  removed  from  the 
system,  the  reaction  will  be  reinaugu rated.  Concentration  or  dilu- 
tion of  the  volume  will  also  disturb  the  apparent  equilibrium,  and  an 
increase  of  temperature  will  cause  the  reaction  to  recommence  in  a 
system  that  had  become  quiescent.  Finally,  the  addition  of  further 
ferment  may  reinaugurate  the  reaction,  although  it  can  easily  be 
shown  that  an  abundance  of  active  ferment  is  still  present  in  the 
mixture.  The  only  possible  direct  interpretation  of  the  last  fact  is  that 
the  ferment  is  reacting  with  the  components  of  the  system,  probably 
with  the  substrate,  and  in  a  relation  of  proportion.  By  repeated  addi- 
tions of  ferment  it  may  be  possible  in  some  instances  to  complete  the 
reaction,  provided  only  that  the  initial  concentration  of  the  system 
was  sufficiently  diluted.  These  various  facts  are  identical  with  those 
that  hold  for  a  translocation  of  the  station  of  equilibrium  in  a  true 
reaction  of  measurable  reversibility,  except  that  in  these  cases  the 
further  addition  of  catalyzer  will  not  shift  the  point  of  equilibrium. 
The  least  difficult  interpretation  is  that  the  ferment  has  entered  into 
reactions  with  the  components  of  the  original  system  and  that  the 
station  of  equilibrium  has  been  shifted  thereby.  The  equilibrium  is  not 
determined  by  the  substrate  and  the  products  alone,  but  by  the  substrate, 
the  products,  and  the  ferment.  The  observation  has  not  been  confined 
to  ferments;  the  condition  occurs  with  inorganic  catalyzers. 

REVERSION    OF   FERMENT    ACTION 

Theoretically  it  is  possible  to  reverse  every  reaction  if  the  appro- 
priate conditions  be  secured.  And,  of  course,  this  applies  to  catalytically 
accelerated  reaction.  The  catalysis  has  only  to  do  with  the  speed  of 
the  reaction,  not  with  the  direction.    The  direction  of  the  reaction  is 


86  THE  THEORY  OF  FERMENT  ACTION 

related  to  the  concentrations  of  the  reacting  masses,  not  to  the  cata- 
lyzer. Just  as  lubrication  will  make  a  locomotive  run  better  either 
backward  or  forward,  so  a  catalyzer  will  make  a  reaction  proceed 
faster  no  matter  in  which  way  the  reaction  is  proceeding.  All  this 
applies  without  qualification  to  enzyme  reactions.  But  the  attain- 
ment of  the  appropriate  conditions  for  reversion  of  reactions  is  often 
very  difficult  and  usually  practically  impossible.  These  difficulties 
are  no  more  inherent  in  fermentations  than  in  reactions  between 
inorganic  or  organic  substances.  To  reverse  the  reaction  for  the 
formation  of  hydrogen  gas  by  the  action  of  sulphuric  acid  on  zinc, 
over  sixteen  atmospheres  pressure  of  hydrogen  gas  is  necessary.  That 
in  practice  it  has  been  impossible  to  reverse  more  than  a  few  ferment 
reactions  in  nowise  reflects  upon  the  doctrine  of  enzymic  reversion 
of  reaction.  When  added  to  the  inherent  difficulties  of  the  subject, 
we  add  the  extremely  unfavorable  property  of  lability  possessed  by 
ferments  in  general,  the  wonder  is  not  that  so  few  ferment  reactions 
have  been  reversed;  the  real  wonder  is  that  they  have  been  reversed 
at  all.  The  usual  expression — reversed  ferment  action — is  a  misnomer. 
It  is  not  the  ferment  action  that  is  reversed;  it  is  the  direction  of  the 
reaction  that  is  reversed  and  the  accelerating  action  of  the  ferment 
makes  this  analytically  demonstrable. 

It  is  in  the  domain  of  the  esters,  the  fats,  that  the  most  successful 
reversions  have  been  accomplished.  Here  the  chemical  relations  are 
relatively  simple.  Through  the  accelerating  action  of  lipases  of  both 
plant  and  animal  origin,  many  different  esters,  both  natural  and  syn- 
thetic, and  natural  neutral  fats  have  been  formed  in  such  amounts 
and  under  such  conditions  of  experimentation  as  to  exclude  any  other 
interpretation  than  reversed  reaction  made  demonstrable  by  the 
accelerating  influence  of  lipase.  If  these  fats  were  not  formed  through 
the  action  of  lipase,  then  fats  have  never  been  digested  through  the 
action  of  lipase;  the  procedures  are  identical  except  for  the  variation 
in  the  relations  of  concentration  of  the  reacting  bodies,  and  the  results 
are  indubitable. 

Results  have  been  attained  also  with  carbohydrates,  but  the  rela- 
tions are  very  complex.  Under  influence  of  maltase  it  is  possible  to 
form  a  disaccharid  from  glucose.  But  the  disaccharid  is  not  maltose, 
it  is  isomaltose.  Now  isomaltose  is  a  substance  that  may  be  formed 
from  starch  by  acids  and  diastatic  ferments.  It  may  also  be  formed 
from  glucose  by  acids.  The  formation  of  isomaltose  instead  of  maltose 
by  ferments  is,  therefore,  not  peculiar  to  the  enzyme  factor,  since 
acid  does  the  same  thing.  It  is  peculiar  to  reversion,  under  the  condi- 
tions employed  up  to  the  present,  but  not  peculiar  to  the  accelerations 
of  the  reversion.  It  is  incorrect  to  blame  the  ferment  for  the  deflec- 
tion, whose  cause  lies  in  some  unknown  conditions  within  the  reaction. 
At  the  same  time  it  is  possible  for  a  catalyzer  or  enzyme  to  modify  the 
products  of  a  reaction  it  is  accelerating.  For  us  the  important  fact 
is  that  under  the  influence  of   ferment,  disaccharid  is  formed    from 


CATALYSIS  IN  HETEROGENEOUS  SYSTEMS  87 

primary  sugar.  Under  the  action  of  acids  and  ferments  poly sacch arid- 
like  bodies  have  also  been  formed  from  hexoses.  But  the  analytical 
findings  are  too  inconclusive  to  mean  much.  The  formation  of  amyg- 
dalin  from  mandel-nitril  glucosid  and  d-glucose  has  been  accomplished 
through  the  action  of  maltase. 

Little  success  has  been  attained  with  proteins.  The  formation  of 
plastein  by  pepsin  cannot  be  regarded  as  a  reversion.  It  has  been 
possible  with  a  trypsin  to  form  from  the  products  of  the  digestion  of 
protamin  a  substance  of  the  percentage  composition,  and  general 
reactions  of  protamin.  There  is  at  present  no  way  of  knowing  whether 
this  substance  be  identical  with  native  protamin  or  an  isomer.  By 
the  action  of  pepsin  certain  of  the  digestion  stages  of  casein  have  been 
reversed.  Beyond  this,  all  experimental  investigations  have  yielded 
failures. 

It  is  necessary  in  judging  investigations  of  enzyme  reversions  to 
bear  constantly  in  mind  what  is  a  general  experience  in  organic  chem- 
istry. In  the  building  up  of  complex  substances,  in  syntheses,  it  is 
easy  to  develop  side  reactions;  there  are  so  many  opportunities  for 
reactions  with  materials  that  are  so  liable.  In  the  disintegration  of 
complex  substances  on  the  other  hand,  the  tendency  to  side  reactions 
is  much  less  pronounced,  the  reactions  tend  to  proceed  with  little 
modification  to  the  components.  Naturally  these  tendencies  would 
hold  with  catalytic  or  enzymic  accelerations  of  the  same  reactions. 


CATALYSIS   IN   HETEROGENEOUS    SYSTEMS 

What  has  been  said  heretofore  applies  specifically  only  to  homo- 
geneous systems.  Now  in  many  reactions  of  fermentation,  as  well 
as  in  many  organic  catalyses,  we  have  to  deal  with  heterogeneous 
systems,  and  very  important  physical  deviations  are  here  presented. 
We  have  furthermore  to  deal  with  different  combinations  of  condi- 
tions. The  substrate  may  be  solid,  the  solvent  fluid  and  the  catalyzer 
fluid.  Or  the  substrate  may  be  in  homogeneous  solution,  while  the 
catalyzer  is  solid.  There  are  even  conditions  in  which  the  products 
may  be  solid,  as  in  the  enzymic  reaction  in  which  amorphous  sulphur 
is  produced  from  hyposulphite.  And,  lastly,  we  have  the  condition, 
common  in  the  world  of  living  matter,  of  a  suspended  colloidal  cata- 
lyzer accelerating  the  reaction  of  a  colloidal  substrate  suspended  in 
water. 

Let  us  first  consider  the  relations  when  the  substrate  is  colloidal 
or  solid,  the  catalyzer  fluid.  When  such  a  body  is  suspended  in  water, 
the  same  relations  hold  that  apply  to  the  conditions  of  solution  of  a 
substance  in  water.  Each  particle  of  the  solid  is  to  be  conceived  as 
surrounded  by  an  infinitely  thin  film  of  saturated  solvent;  and  if  the 
general  bulk  of  the  solvent  be  kept  homogeneous  by  proper  stirring, 
the  velocity  of  solution  will  be  proportional  to  the  difference  between 


88  THE  THEORY  OF  FERMENT  ACTION 

the  concentration  of  a  saturated  solution  and  of  the  particular  satura- 
tion present  in  the  particular  moment,  in  accordance  with  the  formula: 

dx 

—  =  k  (C  -  c), 
dt 

C  being  the  concentration  of  saturation  and  c  that  concentration 
actually  present  in  a  particular  moment.  The  surface  of  the  solid 
must  be  constant. 

If,  on  the  other  hand,  the  substrate  is  fluid  or  soluble  and  the  cata- 
lyzer solid  the  relations  will  be,  so  to  speak,  reversed.  The  reaction 
must  be  conceived  to  occur  only  at  the  film  of  contact  of  the  particle 
with  the  solution,  and  the  substrate  must  be  brought  to  this  film  and 
the  products  removed. 

Systematic  authors  have  in  general  applied  the  law  of  mass  action 
and  the  theory  of  the  order  of  a  reaction  to  heterogeneous  systems, 
the  formula?  being  modified  to  meet  the  complicated  conditions.  Under 
such  circumstances  the  progress  of  the  reaction  is  held  to  take  place 
only  in  the  film  of  contact  between  the  two  phases,  and  is  there  pro- 
portional to  the  dimensions  of  the  surface  of  contact;  but  otherwise  it 
follows  the  general  law  and  is  proportional  to  the  mass  of  the  reacting 
body  or  bodies,  it  being  assumed  that  the  homogeneity  of  the  general 
bulk  of  the  solvent  is  maintained.  It  was  assumed  that  the  time  re- 
quired for  the  diffusion  of  the  reacting  bodies  to  and  from  the  film  of 
contact  was  rapid  in  comparison  to  the  time  required  for  the  reaction. 
Obviously  the  conditions  would  vary  depending  upon  whether  the 
dimensions  of  the  surface  of  contact  are  constant,  increase  or  diminish. 
For  metallic  colloids  the  suspended  particles  may  be  assumed  to  be 
symmetrical,  probably  globular,  and  under  these  conditions  there  is  a 
definite  relation  between  quantity  and  surface;  for  ferments,  however, 
the  shape  of  the  particles  is  probably  amorphous  and  of  no  regular 
symmetry,  so  that  here  the  alteration  in  the  dimensions  of  the  surface 
of  contact  with  the  progress  in  the  reaction  cannot  be  even  surmised. 

Under  present  conceptions  of  the  nature  of  suspensions  of  the 
so-called  stable  colloids,  such  a  colloid  suspended  in  water  forms  two 
phases — a  water-poor  and  a  water-rich  phase,  in  short,  an  aqueous 
and  a  colloidal  phase.  When  a  third  substance  is  dissolved  in  such  a 
two-phase  system,  it  is  distributed  betwreen  the  two.  The  substance 
will  be  taken  up  in  two  ways,  partly  by  adsorption  at  the  film  of  the 
colloidal  phase,  partly  in  solution  in  both  phases.  Now  a  portion  of 
the  substance  that  has  entered  into  the  colloidal  phase  is  irreversibly 
bound;  a  larger  portion,  however,  may  be  withdrawn.  The  coefficient 
of  distribution  of  the  substance  in  the  two  phases  will  depend  in  part 
upon  the  concentrations  and  in  part  upon  the  chemical  relations  that 
determine  for  different  substances  the  extent  of  the  irreversible  combi- 
nation. If,  now,  the  colloid  happens  to  be  a  ferment,  and  the  dissolved 
substance  the  substrate  of  a  fermentation,  it  is  clear  that  the  law  of 


CATALYSIS  IN  HETEROGENEOUS  SYSTEMS  89 

mass  action  cannot  be  applied  to  the  reaction  under  the  simple  assump- 
tion that  the  velocity  of  the  reaction  is  proportional  to  the  active  mass 
of  the  substrate  and  to  the  dimensions  of  the  film  of  contact:  In  such 
an  experiment,  account  must  be  taken  of  the  factor  of  the  coefficient 
of  distribution,  and  also  of  the  velocity  with  which  this  distribution 
is  effected,  since  with  the  progress  of  the  reaction,  this  would  be  of 
influence.  If  both  the  substrate  and  the  ferment  be  stable  colloids, 
the  situation  would  be  only  the  more  complicated.  The  difference 
between  the  stable  (hydrophilic)  colloids,  like  starch  and  protein  and 
the  unstable  (suspension)  colloids,  like  the  metallic  suspensions,  must 
never  be  overlooked;  and  they  are  associated  with  such  pronounced 
differences  in  physical  behavior  that  we  are  not  permitted  to  apply 
directly  to  the  stable  colloids  the  results  of  investigations  with  unstable 
colloids.  While,  therefore,  it  must  be  conceded  that  the  law  of  mass 
action  cannot  be  applied  to  fermentations  in  the  full  theoretical  sense, 
the  actual  question  is :  To  what  extent  do  the  factors  of  the  coefficient 
and  velocity  of  distribution  produce  deviations  in  the  operation  of  the 
law  of  mass  action  ?  This  is  a  question  for  experimentation,  and  there 
is  very  little  data  bearing  upon  it.  It  is  certain  that  the  relations 
are  different  in  different  fermentations. 

In  many  instances,  however,  it  is  clear  that  the  velocity  of  reaction 
at  the  film  of  contact  is  much  more  rapid  than  is  the  diffusion  of  the 
reacting  bodies  to  and  of  the  products  from  the  film.  We  may  state 
this  point  of  view  in  the  contemplation  of  the  velocity  of  reactions 
in  heterogeneous  systems,  by  amplifying  the  principle  of  the  solution 
velocity  to  include  the  apparent  velocity  of  reaction,  and  to  define 
just  what  an  experimental  velocity  in  a  heterogeneous  system  really 
means.  There  are  obviously  three  main  processes  in  such  a  reaction — 
the  passage  of  the  substance  through  the  surface  of  contact  between 
the  two  phases,  the  boundary  film;  the  chemical  reaction  in  one  of  the 
two  phases;  and  diffusion  to  and  away  from  the  boundary  film.  The 
first  process  occurs  with  such  rapidity  as  to  have  no  influence  upon 
the  relations.  If  the  reaction  be  rapid  as  compared  to  the  diffusion, 
equilibrium  will  exist  at  the  surface  of  contact;  and  if  proper  mixing 
be  provided,  the  velocity  of  reaction  represents  simply  the  velocity 
of  diffusion  of  substances  to  and  from  the  surface  of  contact. 

The  point  of  view  is  best  stated  in  the  words  of  Nernst:  "Many 
facts  have  led  to  the  assumption  that  equilibrium  is  established  with 
extraordinary  rapidity  at  the  surface  of  contact  of  two  phases.  Such 
a  condition  is  indeed  a  theoretically  natural  assumption,  because  at 
the  surface  of  separation  of  two  phases,  as  infinitely  approximated 
points,  marked  differences  in  chemical  potential  would  appear,  and 
these  would  obviously  produce  much  chemical  energy  and  lead  to 
great  rapidity  of  reaction.  This  means  nothing  more  than  in  each 
moment  the  equilibrium  is  established  very  rapidly  in  the  immediate 
neighborhood  of  the  surface  of  separation.  If  one  assumes,  what  is 
mathematically  more  probable,  that  the  surface  of  contact  is  not  a 


90  THE  THEORY  OF  FERMENT  ACTION 

mathematical  point  but  rather  a  narrow  area  of  transition,  we  are 
nevertheless  still  concerned  with  dimensions  of  the  order  of  the  sphere 
of  activity  of  molecular  potentials;  and  though  we  can  then  no  longer 
speak  of  an  infinite  velocity  of  reaction,  we  will  still  be  dealing  with 
such  velocities  as  are  for  practical  purposes  infinite.  When  we  con- 
sider a  chemical  reaction  from  this  point  of  view,  for  example,  the 
solution  of  magnesia  in  dilute  acids,  we  assume  that  the  magnesia  is 
in  each  moment  in  equilibrium  with  the  solution,  i.  e.,  the  solution 
in  immediate  proximity  to  the  magnesia  is  saturated  and,  therefore, 
alkaline.  The  diffusing  acid  will  be  entirely  neutralized  at  the  surface 
of  contact;  the  velocity  of  solution  of  the  magnesia  depends  solely 
upon  the  velocity  with  which  the  acid  diffuses  to  the  layer  of  contact 
of  solvent  and  magnesia. 

"In  recent  time  the  van't  Hoff  theory  of  the  order  of  a  reaction, 
i.  e.,  the  deduction  of  the  number  of  reacting  molecules  from  the  progres- 
sion of  a  reaction,  has  been  often  applied  to  reactions  in  heterogeneous 
systems.  When  one  considers  that  this  theory  rests  upon  the  calcula- 
tion of  the  probability  of  the  kinetic  collision  of  two  or  more  molecules 
in  the  gaseous  state  or  in  dilute  solution,  it  becomes  clear  that  there 
is  no  sense  in  its  application  to  heterogeneous  systems,  or  at  least 
that  there  is  for  such  application  no  theoretical  foundation  extant. 
The  above-mentioned  considerations,  however,  teach  us  that  the 
application  of  the  van't  Hoff  theory  to  heterogeneous  systems  is  not 
only  without  direct  foundation,  but,  indeed,  entirely  improper,  because 
in  reactions  in  a  heterogeneous  system,  in  so  far  as  the  reactions  occur 
only  at  the  surface  of  contact  of  the  two  phases,  the  velocity  is  partly 
or  entirely  dependent  upon  the  velocity  of  diffusion,  which  has  no 
connection  with  the  order  of  reactions. 

"A  special  instance  of  heterogeneous  chemical  reactions  is  afforded 
by  the  accelerations  of  reactions  by  colloidal  catalyzers  such  as  plati- 
num-asbestos, Bredig  solutions,  etc.  Since  these  reactions  probably 
progress  solely  upon  the  surface  of  the  catalyzer,  the  velocity  will  in 
no  way  depend  upon  the  mechanism  of  the  particular  reaction;  if  the 
catalyzer  maintains  its  integrity  through  the  course  of  the  reaction 
(which  cannot  be  foreseen  in  advance),  and  carries  through  its  reac- 
tion on  the  surface  of  contact  with  practically  infinite  rapidity,  the 
velocity  will  depend  upon  the  diffusion  of  the  reacting  bodies  to  the 
catalyzer." 

That  this  reasoning  need  not  hold  true  in  chemical  reactions  of  this 
type  is  illustrated  by  the  electrolytic  reduction  of  nitrobenzene;  the 
reaction  at  the  surface  of  the  electrode  was  found  to  be  slow  compared 
with  the  velocity  of  diffusion  to  the  electrode.  As  contrasted  with  the 
total  denial  of  the  application  of  the  kinetic  theory  of  the  order  of  a 
reaction  to  a  heterogeneous  system,  it  may  be  pointed  out  that  the 
Brownian  movements  in  the  particles  of  a  colloid  are  proportional 
to  the  molecular  movements  postulated  in  a  homogeneous  solution 
by  the  kinetic  theory.     The  general  proposition  that  chemical  reac- 


CATALYSIS  IN  HETEROGENEOUS  SYSTEMS  91 

tions  must  occur  with  infinite  velocity  in  the  film  of  contact  of  two 
phases  has  also  been  denied  on  thermodynamic  and  experimental 
grounds. 

While  it  is  too  early  to  pass  judgment  upon  this  theory,  whose  funda- 
mental import  to  biology  must  be  apparent,  several  general  considera- 
tions may  be  pointed  out.  One  is  that  the  relations  in  fermentations 
will  be  much  more  complex,  because  we  have  here  often  a  colloidal 
substrate  and  a  colloidal  ferment  suspended  in  water  instead  of  having 
a  heterogenicity  dependent  upon  only  one  member  of  the  system. 
Since  in  the  case  of  a  colloidal  substrate  the  reaction  is  held  to  occur 
on  the  surface  of  its  particles,  and  in  the  case  of  a  colloidal  catalyzer 
the  reaction  is  held  to  occur  on  the  surface  of  its  particles,  when  these 
conditions  are  united  in  one  system,  the  reaction  ought  to  be  very 
slow;  experience,  however,  has  taught  us  that  some  of  these  reactions 
are  quite  rapid.  Secondly,  the  reasoning  is  based  upon  the  assump- 
tion that  the  solid  body  is  so  slightly  soluble  in  the  medium  of  the 
reaction  that  it  does  not  participate  appreciably  in  the  diffusion.  This 
condition  will  in  all  probability  be  found  not  to  hold  good  for  many 
of  the  pseudocolloidal  substrates  employed  in  fermentations.  Thirdly, 
the  theory  assumes  that  the  catalyzer  is  not  altered  in  the  course  of  the 
reaction,  whereas  in  most  fermentations  the  contrary  is  the  case. 

An  argument  against  this  theory  lies  in  the  temperature  coefficient 
of  fermentations.  The  velocity  of  chemical  reactions  is  greatly  acceler- 
ated by  increase  in  temperature;  the  velocity  of  diffusion  only  slightly. 
Now  in  the  case  of  most  ferments  an  increase  in  temperature  is  followed 
by  the  increase  in  velocity  that  would  be  expected  in  a  chemical  reac- 
tion— it  is  usually  more  than  doubled  in  10° — far  more  than  would 
be  expected  were  a  process  of  diffusion  alone  concerned.  This  suggests 
that  there  is  a  small  portion  of  the  colloidal  substrate  and  colloidal 
ferment  in  true  solution,  and  that  the  reaction  is  concerned  with 
these. 

Another  objection  is  that  proportional  increases  in  viscosity  in  the 
fermenting  system,  due  to  the  addition  of  different  substances,  ought 
to  exert  proportional  retardations  of  velocity  if  that  velocity  express 
simply  the  diffusion  velocity.  This  is  not  the  case.  Similarly,  in 
heterogeneous  reactions  of  known  chemical  nature,  variations  in  con- 
centration and  viscosity  ought  to  produce  the  same  variations  in 
velocity  as  in  fermentation  experiments;  but  this  has  not  been  observed 
to  be  true. 

Lastly,  it  must  be  again  pointed  out  that  the  term  colloid  does  not 
correspond  to  a  fixed  quality,  but  to  a  tendency  to  physical  qualities 
that  is  more  or  less  pronounced  in  different  substances.  For  Graham 
the  colloid  was  the  non -diffusible  body,  the  crystalloid  the  diffusible 
body.  Colloids  confer  upon  their  solutions  or  suspensions  a  very  slight 
depression  of  the  freezing  point  or  elevation  of  the  boiling  point,  and 
possess  a  very  low  osmotic  pressure,  all  of  which  indicate  that  the 
work  necessary  to  effect  the  separation  of  the  colloid  from  the  medium 


92  THE  THEORY  OF  FERMENT  ACTION 

is  small;  with  crystalloids  the  contrary  is  true.  Like  all  suspensions, 
even  the  hydrophilic  colloidal  solutions  display  peculiar  conditions  of 
precipitation  and  coagulation,  and  are  very  active  in  all  that  relates 
to  surface  tension  and  adsorption.  But  it  is  not  at  all  true  that  all 
chemical  bodies  belong  to  one  or  to  the  other  of  these  classes.  On 
the  contrary,  there  are  innumerable  intermediary  conditions,  corres- 
ponding to  all  conceivable  gradations  from  the  typical  crystalloid  to 
the  typical  colloid.  Not  only  this,  many  substances  display  attributes 
quite  extreme;  thus  protamin  will  not  crystallize,  but  does  diffuse 
well  and  will  transport  an  electrical  current,  while  some  higher  proteins 
will  crystallize  and  yet  not  diffuse  with  measurable  rapidity;  and  some 
are  quite  insoluble  in  the  true  sense,  while  others  are  quite  soluble. 
Under  these  circumstances,  dealing  with  bodies  displaying  all  degrees 
of  gradation  from  the  typical  crystalloid  to  the  typical  colloid,  it  is 
difficult  to  foresee  to  what  extent  this  theory  based  upon  the  qualities 
of  practically  pure  heterogenicity  in  the  system  will  bear  the  test  of 
experimental  application  to  fermentations.  The  hydrophilic  colloids 
with  which  we  are  dealing  in  fermentations  are  in  many  respects  different 
from  the  metallic  suspensions  to  which  the  theory  finds  direct  applica- 
tion. They  react  differently  to  electrolytes,  resist  precipitation  by 
them,  are  indeed  in  some  instances  protected  from  precipitation  by 
them,  and  they  have  the  power  to  protect  genuine  colloids  from  pre- 
cipitation by  electrolytes.  Under  ultramicroscopic  examination, 
the  stable  hydrophilic  (or  pseudo)  colloids  are  seen  to  possess  much 
smaller  particles  than  the  true  or  suspension  colloids  and  correspond- 
ing to  this  they  tend  to  display  crystalloid  tendencies — power  of  diffu- 
sion, osmotic  pressure,  etc.  In  fact,  some  of  the  proteins  have  as  pro- 
nounced crystalloid  properties  as  many  dyestuffs  (which  are  commonly 
considered  as  crystalloids),  and  scarcely  more  measurable  colloidal 
properties.  Obviously  the  hypothesis  cannot  be  applied  to  such  bodies 
with  complete  theoretical  validity.  That  the  conditions  upon  which 
this  theory  is  based  will  often  be  of  great  influence  in  the  progression 
of  reactions  must  be  conceded  in  advance;  it  is  indeed  a  priori  probable 
that  in  many  instances  the  experimental  velocity  will  be  the  result  of 
both  a  true  reaction  velocity  and  the  diffusion  velocity;  but  whether 
the  theory  will  afford  an  adequate  explanation  of  all  the  phenomena 
is  very  much  to  be  doubted  so  far  as  biological  fermentations  are  con- 
cerned. The  results  in  many  instances  correspond  very  closely  with 
the  requirements  of  the  older  law.  In  other  instances,  however,  such 
conformity  has  not  been  obtained,  and  it  may  be  precisely  in  these 
cases  that  the  conditions  stated  have  played  predominating  roles. 
The  velocity  of  cleavage  of  an  insoluble  fat  by  lipase  represents  a 
probable  illustration  of  a  diffusion  velocity. 

Another  factor  which  must  modify  the  relations  in  the  complex 
fermentations  of  biological  order  is  the  relation  of  colloids  to  each 
other.  The  adsorption  of  stable  colloids  by  one  another  is  not  solely 
a  function  of  surface  tension;  it  is  in  part  at  least  a  function  of  composi- 


CATALYSIS  IN  HETEROGENEOUS  SYSTEMS  93 

tion.  The  adsorptions  of  a  particular  colloid  by  two  different  colloids 
even  of  the  same  surface  tension  are  not  identical.  It  is  the  usual 
teaching  that  colloids  cannot  diffuse,  but  the  phenomena  of  adsorption 
throw  grave  doubt  upon  this  statement.  Colloidal  hydrosols  will 
penetrate  hydrogels  in  a  progressive  linear  manner.  That  this  may 
not  be  a  true  diffusion,  but  rather  a  co-solution,  a  relation  of  the 
coefficient  of  distribution,  possibly  even  a  chemical  combination  with 
the  formation  of  a  new  colloidal  complex,  is  freely  granted.  But  the 
fact  will  no  less  indicate  that  the  phenomenon  under  whatever  name 
it  passes  must  constitute  a  variable  in  the  reactions  in  such  a  system. 

It  is  necessary  further  to  consider  the  nature  of  the  relations  between 
the  substrate  and  the  ferment.  We  know  on  the  one  hand  that  colloids 
enter  into  complex  chemical  combinations  with  other  substances. 
We  have  evidence  that  complex  combinations  of  this  sort  occur  in 
the  body;  such  are  the  sugar-protein,  the  protein-fat,  the  nucleo- 
protein,  the  lecethin-protein  complexes.  These  are  destined  to  play 
a  most  important  role  in  the  chemical  physiology  of  the  future.  As 
chemical  combinations  these  complexes  are  subject  to  the  laws  of 
mass  action,  equilibrium,  and  partition.  On  the  other  hand,  we  know 
that  colloids  form  with  other  substances  physical  equilibria  that  are 
termed  adsorption  compounds.  Recent  investigations  seem  to  indicate 
that  for  the  typical  unstable  colloids  (metallic  hydrosols,  silicate,  etc.) 
the  laws  of  mass  action,  equilibrium  and  partition  do  not  hold.  For 
the  atypical  hydrophilic  colloids  (protein,  starch,  etc.)  these  laws 
tend  to  hold.  It  is  fairly  certain  that  for  some  reactions  (e.  g.,  the 
system  dye-cellulose)  the  early  occurrence  of  secondary  reactions  affect- 
ing the  one  component  (the  dye)  is  responsible  for  the  non-fulfilment 
of  these  laws  and  the  cause  of  the  irreversibility  of  the  reaction;  such 
a  phenomenon,  however,  does  not  constitute  a  fundamental  exception 
to  the  laws.  Concerning  these  matters  we  possess  as  yet  so  little  quan- 
titative data  that  definite  conclusions  are  not  warranted.  Nevertheless, 
until  we  can  conceive  that  two  substances  meeting  in  a  thin  film  on 
the  surface  of  a  third  indifferent  substance  react  with  infinite  velocity, 
we  shall  be  compelled  to  consider  the  combination  of  ferment-substrate 
to  be  of  the  nature  of  a  chemical  complex  rather  than  of  a  physical 
adsorption  compound. 

In  its  broadest  application,  the  fact  that  reactions  occur  with  great 
velocity  at  the  boundary  of  contact  of  two  phases  must  appeal  to 
everyone  as  a  fact  of  the  deepest  biological  significance.  When  we 
consider  that  the  cells  of  the  body  in  their  relations  to  the  circulating 
fluids,  indeed  the  fibrillar  and  granular  parts  of  cells  in  their  relations 
to  the  intercellular  fluids,  represent  precisely  just  such  two-phase 
systems,  we  realize  the  magnitude  of  the  factor  with  which  we  are 
dealing.  From  the  physical  point  of  view,  the  cellular  constructions  are 
colloidal  phases,  hydrogels;  the  body  fluids  watery  phases,  hydrosols. 
The  magnitude  of  the  dimensions  of  the  boundaries  of  contact  of  the 
two  phases  in  a  human  body  is  almost  inconceivable;  and  the  influence 


94  THE   THEORY  OF  FERMENT  ACTION 

upon  the  velocity  of  a  reaction  under  these  circumstances  contrasted 
with  the  velocity  of  a  reaction  in  a  homogeneous  system  of  the  same  bulk 
must  be  enormous.  Though  it  is  a  pure  speculation,  one  cannot  refrain 
from  entertaining  the  thought  that  to  this  factor  may  be  ascribed, 
in  part  at  least,  the  great  difference  in  velocity  everywhere  to  be 
observed  between  reactions  in  vivo  and  in  vitro. 


THE   NATURE   OF   FERMENTS 

We  know  very  little  of  the  chemical  nature  of  ferments.  They  are 
always  associated  with  numerous  bodies  derived  from  the  cells  to  which 
they  owe  their  origin,  and  they  are  so  labile  that  isolation  is  attended 
with  denaturation  and  decomposition.  We  may  say  that  ferments  are 
proteins,  or  closely  resemble  them.  This  general  conclusion  is  based 
upon  the  facts  that  ferments  are  usually  coagulable;  they  respond 
to  the  color  tests  and  reactions  for  protein;  they  are  precipitated  by 
the  ordinary  salts,  and  they  yield  on  hydrolysis  or  digestion,  to  which 
they  are  all  more  or  less  susceptible,  amino-acids.  These  observances 
are,  however,  alike  in  the  case  of  no  two  ferments.  Their  physical 
properties  likewise  vary.  Some  are  very  colloidal,  others  diffuse. 
Some  rotate  the  plane  of  polarized  light,  and  are  thus  known  to  con- 
tain asymmetrical  carbon ;  others  are  optically  inactive.  Some  contain 
a  carbohydrate  moiety,  and  thus  appear  to  resemble  glycoproteids. 
Others  contain  a  large  amount  of  phosphorus  in  organic  combination,  on 
digestion  yield  purin  bodies  and  thus  appear  to  resemble  nucleopro- 
teids.  In  fact,  the  best  studied  of  the  animal  ferments,  pepsin,  exhibits 
these  qualities.  Other  ferments  contain  no  nuclein  or  carbohydrate, 
are  not  coagulable,  and  resemble  proteose.  Thus,  only  the  most  tenta- 
tive opinions  may  be  passed  upon  the  chemical  nature  of  these  bodies. 


THE   MODUS    OPERANDI   OF  FERMENTATION 

A  discussion  of  the  chemical  basis  of  enzymic  acceleration  must  in 
the  nature  of  the  phenomenon  be  based  primarily  upon  a  study  of  the 
nature  of  catalytic  accelerations  in  general,  and  upon  the  demonstra- 
tion of  analogies  and  reactional  relations  existing  between  them.  Since 
it  seems  certain  from  the  thermodynamic  point  of  view  that  a  catalyzer 
or  ferment  acts  only  by  direct  or  indirect  reduction  of  the  internal 
resistance,  and  not  by  any  increase  in  the  driving  force  of  the  reaction, 
all  investigations  must  be  directed  to  the  internal  physical  and  chemical 
resistance. 

In  the  consideration  of  the  modus  operandi  of  the  catalytic  accelera- 
tion, we  thus  face  directly  the  question  of  the  nature  of  the  internal 
resistance  to  chemical  reactions  that  is  a  property  of  all  substances. 
Since  a  catalytic  acceleration  is  defined  as  an  acceleration  due  to  the 


THE  MODUS  OPERANDI  OF  FERMENTATION  95 

lowering  of  the  internal  resistance  of  the  substance,  we  must  attempt 
to  define  a  conception  of  chemical  resistance.  There  has  been  little 
study  of  this  aspect  of  the  question.  Of  the  two  factors  in  every  reac- 
tion— the  driving  force  and  the  internal  resistance — nearly  all  the 
physico-chemical  research  has  been  directed  to  the  driving  force. 
That  the  constitution  of  organic  molecules  is  associated  with  varia- 
tions in  the  resistance  to  reactions  is,  of  course,  well  known.  But 
the  same  factor  of  resistance  resides  in  the  most  simple  inorganic 
substance.  In  any  event,  it  is  certain  that  the  term  internal  resistance 
stands  not  for  one  thing,  but  may  stand  for  many  things  that  are  varied 
from  case  to  case.  Under  these  circumstances,  therefore,  the  means 
whereby  a  catalytic  agent  lowers  this  resistance  may  vary  from  case 
to  case,  and  must  be  studied  anew  for  each  individual  reaction.  One 
of  the  future  achievements  in  chemistry  will  be  to  define  an  Ohm's  law 
for  chemical  reactions. 

There  are  several  ways  in  which  the  presence  of  a  catalyzer  might 
accelerate  the  velocity  of  a  reaction.  Firstly,  it  might  reduce  the 
chemical  resistance  of  a  substance  just  as  temperature  does.  Secondly, 
it  might  reduce  the  number  of  intermediate  stages  that  occur  naturally 
in  the  reaction.  An  illustration  of  this  in  the  domain  of  inorganic 
chemistry  is  to  be  seen  in  the  action  of  a  cobalt  salt  on  the  reaction 
between  NaOH  and  CI.  This  would  amount  to  a  short  cut  to  the 
final  product,  and  if  the  velocity  of  each  step  were  no  greater  than 
in  the  ordinary  reaction,  the  total  velocity  would  be  greater.  Thirdly, 
new  intermediary  reactions  might  be  introduced,  of  greater  velocity,  so 
that  the  sum  of  their  velocities  would  be  greater  than  the  velocity  of 
the  original  reaction.  A  quantitative  illustration  of  this  is  to  be  found 
in  the  acceleration  of  the  reduction  of  hydrogen  peroxid  by  hydriodic 
acid  under  the  catalytic  influence  of  molybdic  acid. 

Theory  of  Intermediary  Reactions. — The  theory  of  intermediary 
reactions  is  not  only  the  oldest  theory,  it  has  also  in  its  favor  a  large 
amount  of  experimental  evidence.  The  theory  is  in  brief  that  a  cata- 
lyzer accelerates  the  velocity  of  a  reaction  by  the  introduction  of 
intermediary  reactions  with  the  formation  of  unstable  products,  usually 
of  the  type  of  addition  products;  that  these  products  are  themselves 
so  unstable  that  they  disintegrate  of  their  own  accord  or  they  are 
disintegrated  by  the  action  of  other  bodies  in  the  system;  and  that 
the  sum  of  the  velocities  of  the  several  reactions  is  greater  than  the 
velocity  of  the  primary  reactions.  The  theory  has  been  tested  solely 
upon  catalyses  of  pure  reactions,  usually  of  inorganic  nature.  Thus  far 
the  evidence  is  almost  entirely  qualitative;  in  investigations  upon  the 
acceleration  of  the  reaction  between  hydrogen  peroxid  and  hydriodic 
acid  by  molybdic  acid,  however,  the  kinetic  relations  were  worked  out 
in  such  a  manner  as  to  demonstrate  that  the  sum  of  the  velocities  of 
the  several  reactions  is  greater  than  the  velocity  of  the  natural  reaction. 

It  is  usually  assumed  that  even  the  simplest  reactions  are  not  accom- 
plished directly;  they,  too,  pass  through  intermediary  stages;  and  thus 


06  THE  THEORY  OF  FERMENT  ACTION 

the  catalyzer  by  the  introduction  of  other  intermediary  stages  does 
not  in  the  least  alter  the  general  nature  of  the  process  of  reaction, 
but  by  introducing  intermediary  reactions  with  lower  chemical  resist- 
ance effects  a  short  cut  to  the  stage  of  equilibrium.  Experimental 
researches  indicate  that  while  in  some  of  these  accelerations  the  number 
of  intermediary  reactions  is  increased,  instances  are  known  in  which 
the  number  of  intermediary  reactions  has  been  diminished.  In  any 
event,  be  the  number  in  the  catalytic  series  greater  or  less,  the  theory 
assumes  that  the  sum  of  their  velocities  is  greater  than  was  the  velocity 
of  the  original  reaction.  Obviously  the  theory  can  be  properly  tested 
only  upon  a  reaction  for  which  we  can  determine  the  intermediary 
reactions  with  and  without  the  catalyzer.  These  intermediary  reac- 
tions are  to  be  studied  from  the  standpoint  of  the  Ostwald  law  of 
reaction  stages.  In  all  chemical  reactions  the  most  stable  condition 
is  not  attained  at  once,  but  either  the  nearest  reaction  is  attained  or 
among  several  possible  reactions  the  most  unstable,  etc. 

Thus,  CuS04  +  2KOH  =  K2S04  +  CuO  +  H20  passes  through 
one  intermediary  stage. 

CuS04  +  2  KOH  =  K2S04  +  Cu(OH)2 
Cu(OH)2  -  CuO  +  H20 

When  to  such  a  system  an  appropriate  positive  catalyzer  is  added, 
new  intermediary  stages  are  introduced,  termed  for  a  certain  large 
class  of  reactions,  stages  of  primary  oxids;  the  primary  oxids  have 
some  of  the  behaviors  of  peroxids;  they  are  stronger  oxidizers  than 
the  highest  stable  oxidation  stage  and  stronger  reducers  than  the  lowest 
oxidation  stage. 

2  H202  =  2  H20  +  02 

In  the  presence  of  ferric  oxid  this  reaction  is  very  rapid. 

2  H202  +  Fe203  =  iron  primary  oxid  (Fe20302)  +  2  H20 
Fe20302  =  Fe203  +  02 

A  reaction  in  more  stages  is  as  follows : 

4  NaOH    +  2  Cl2  =  4  NaCl  +  2  H20  +  02 

24NaOH    +  12  Cl2  =  12  H20  +  12  NaCl  +  12  NaCIO 
12NaC10    =  8  NaCl  +  4  NaC103 

4  NaC103  =  NaCl  +  3  NaC104 

3NaC104  =  3  NaCl  +  6  02 

Here  there  are  three  stages  of  primary  oxids,  and  each  more  "primary" 
than  the  succeeding  one.  When  a  cobalt  salt  is  added  the  reaction  is 
accelerated. 

24  NaOH  +  12C12  =  12  NaCl  +  12  H20  +  12  NaCIO 

12  NaCIO  +  cobalt  salt  =  12  NaCl  +  cobalt  primary  oxid 
Cobalt  primary  oxid  =  cobalt  salt  +  6  02 


THE  MODUS  OPERANDI  OF  FERMENTATION  97 

Here  all  the  NaCl  are  formed  in  the  first  and  second  stages;  that  is, 
the  number  of  intermediary  reactions  is  reduced. 

The  reaction  of  potassium  permanganate  with   hydrochloric  acid 
has  its  direct  expression  in  the  following  formula: 

KMn04  +  8HC1  =  KC1  +  MnCl2  +  4H20  +  5  CI 

Platinic  chlorid  accelerates  this  reaction  in  the  following  way: 

KMn04  +  4H2PtCl6  =  KC1  +  MnCl2  +  4  PtCl4  +  4H20  +  5  CI 

The  platinic  chlorid  having  combined  with  the  hydrochloric  acid  to 
form  the  chloroplatinic  acid  H2PtCle,  which  is  more  rapidly  reacted 
upon  by  permanganate  than  is  hydrochloric  acid. 

The  reaction  between  hydrogen  peroxid  and   hydriodic  acid  is  ex- 
pressed in  the  following  equation: 

H202  +  2  HI  =  2  H20  +  I2 

H202  +  I-  =  H20  +  01- 

01-    +  2  H+  +  I-  =  H20  +  I2 

When  molybdic  acid  is  added  to  the  system  we  have,  expressed  in  its 
simplest  terms: 

H202  +  H2Mo04  =  H4Mo06 

H4Mo06  +  2  HI  =  H2Mo04  +  2H20  +  I2 

The  sum  of  the  velocities  of  these  reactions  is  very  much  greater  than 
in  the  original  reaction. 

When  hydrogen  peroxid  acts  as  an  oxidizing  agent  it  first  combines 
with  the  substance  to  form  an  unstable  peroxid-like  body. 
Thus, 

H2S03  +  H202  -  H4S05 
H4S05  =  H2S04  +  H20 
And 

Ag20  +  3  H202  =  H4Ag206  +  H20 
H4Ag206  =  2  Ag  +  2  H20  +  2  02 

Theory  of  Induction. — Closely  related  to  the  theory  of  intermediary 
reaction  is  the  theory  of  induction.  When  two  reactions  are  going  on 
in  the  same  solution,  the  presence  of  one  may  accelerate  the  velocity  of 
the  other.  On  close  analysis  it  is  seen  that  the  actual  process  is  one 
of  intermediary  reaction.  All  instances  of  reaction  by  induction  are, 
of  course,  not  catalytic,  but  many  of  them  cannot  be  otherwise  defined 
on  account  of  the  existence  of  a  slow  primary  reaction.  Theoretically, 
induced  reactions  may  be  divided  into  two  groups:  Those  in  which 
the  intermediary  products  are  stable,  and  those  in  which  they  are 
labile.  In  catalyses  we  have  apparently  to  deal  with  those  in  which 
the  intermediary  reactions  are  labile.  The  two  bodies  in  the  reaction 
7 


98  THE  THEORY  OF  FERMENT  ACTION 

whose  presence  results  in  the  acceleration  (the  primary,  voluntary 
reaction)  are  termed  the  inductor  and  the  actor,  while  the  body  whose 
reaction  is  induced  to  an  acceleration  is  termed  the  acceptor,  the  actor 
being  the  same  in  each  reaction.  The  intermediary  body  may  be  either 
a  combination  of  the  actor  with  the  inductor,  or  it  may  be  an  unstable 
addition  product  of  the  actor  or  of  the  inductor.  Good  illustrations 
may  be  given  from  the  group  of  oxidations,  though  the  phenomenon  is 
not  at  all  confined  to  oxidations;  it  is,  on  the  contrary,  in  all  probability 
a  phenomenon  of  widespread  occurrence  and  importance.  The  simplest 
type  is  where  the  acceptor  D  is  slowly  reacting  with  the  actor  A;  when 
the  inductor  I  is  added  it  also  reacts  with  the  actor  A,  and  then  the 
product  reacts  with  the  acceptor  D,  as  a  result  of  which  the  actor  A 
associated  with  I  is  transferred  to  D;  that  is,  I  induces  more  of  A  to 
react  with  D  than  before. 


D    +  A  =  DA  —  very  slow 

I     +  A  =  I A  —  very  rapid;  then 

IA  +  D  =  I  +  DA 


so  that  the  velocity  of  the  formation  of  DA  is  increased. 

The  reaction  S02  +  O  =  S03  is  very  slow.  When  in  the  system, 
however,  the  reaction  ferrous  salt  +  oxygen  =  ferric  salt  is  going  on, 
the  combination  of  the  sulphur  dioxid  is  greatly  accelerated.  The 
reaction  between  the  iron  salts  acts  as  the  carrier  of  oxygen;  as  fast 
as  the  ferric  oxid  is  formed  it  is  reduced  by  the  sulphur  dioxid. 

S02  +  O       =  S03  -  slow 
2FeO  +  02      =  2Fe02  (possibly  Fe206)  rapid;  then 
S02  +  Fe02  =  S03  +  FeO 

The  reaction  from  the  ferrous  to  the  ferric  salt  must  be  kept  going  by 
an  appropriate  catalyzer.  Many  of  the  induced  reactions  are  not  so 
simple,  in  that  there  is  no  reaction  between  the  product  of  the  second 
reaction  and  the  acceptor.  For  example,  chromic  acid,  or  its  salts, 
is  not  able  to  oxidize  tartaric  acid  with  measurable  velocity;  it  oxidizes 
arsenous  oxid  with  great  rapidity.  When  the  two  reactions  are  accom- 
plished in  the  same  system  the  tartaric  acid  is  also  oxidized. 

Chromic  acid  +  tartaric  acid     =  formic  acid  and  other  acids  —  very  slow 
f  Chromic  acid  +  arsenous  acid    =  arsenic  acid  —  very  rapid 
I  Chromic  acid  +  tartaric    acid    =  formic  acid  —  rapid 

Here  the  product  of  the  primary  reaction,  arsenic  acid,  is  stable;  when 
the  reaction  is  completed  the  arsenous  acid  is  entirely  oxidized,  the 
tartaric  acid  in  large  part.  The  relations  have,  therefore,  not  been 
those  of  an  oxygen  carrier,  as  in  the  first  illustration.  The  explanation 
is  that  some  intermediary  stage  in  the  reaction  chromic  acid  +  arsenous 


THE  MODUS  OPERANDI  OF  FERMENTATION  99 

acid  provides  the  point  of  departure  for  the  impetus  of  the  second 
reaction.     This  may  be  represented  as  follows: 

Chromic  acid  +  arsenous  acid  =  intermediary  product  =  arsenic  acid 
Intermediary  product  +  tartaric  acid  =  formic  acid,  etc. 

Another  illustration  is  furnished  by  bromic  acid,  which  does  not  act 
upon  arsenous  acid,  but  reacts  rapidly  with  sulphurous  acid;  when 
the  reactions  are  associated,  the  arsenous  acid  is  also  oxidized. 

As  the  subject  of  inductions  is  investigated,  it  becomes  apparent 
that  many  of  the  accelerations  by  intermediary  reactions  are  of  this 
nature.  All  the  activations  of  oxygen,  in  which  the  formation  of 
peroxid-like  bodies  is  probable,  belong  to  the  simpler  reactions  by 
induction.  Indeed,  the  coupled  reactions  should  be  a  subclass  of  the 
transformations  by  intermediary  reactions.  It  will,  on  the  contrary, 
not  be  possible  to  class  all  the  catalyses  as  induced  reactions,  numerous 
and  important  as  these  certainly  are.  The  process  seems  to  follow  one 
of  two  relations,  depending  upon  whether  the  intermediary  stage  is 
stable  or  labile.  And  of  the  latter,  the  intermediary  stage  that  acts 
as  the  accelerator  to  the  induced  reactions  may  be  either  a  combina- 
tion of  the  actor  with  the  inductor,  or  a  higher  oxidation  stage  of  the 
actor  or  the  inductor. 

A  closely  analogous  condition  in  the  organic  world  seems  to  lie  in 
the  phenomenon  of  the  action  of  acids  upon  the  formation  of  isomers  of 
cinchonin.  When  cinchonin  is  exposed  to  the  action  of  hydrochloric  acid 
(or  other  halogens),  one  isomeric  base  is  produced,  the  a-z-cinchonin, 
and  the  HC1  addition  product  of  cinchonin. 

HCl-cinchonin  (addition  reaction) 
Cinchonin  +  HC1  =  <^ 

a-i-cinchonin  (transformation  reaction) 
Secondary  reactions :   a-z-cinchonin  +  HC1  =  HC1  —  a-i-cinchonin 

The  first  idea  would  naturally  be  that  the  addition  product  represented 
the  intermediary  stage.  However,  it  may  be  shown  that  the  addition 
product  with  HC1  is  not  to  be  converted  into  HC1  and  the  isomeric 
base  under  the  conditions  of  the  experiment.  When  HC1  and  cinchonin 
are  brought  into  a  system  two  reactions  occur,  probably  in  definite 
proportions  and  in  accordance  with  the  law  of  mass  action;  the  end 
products  of  the  two  reactions  are,  firstly,  the  HC1  addition  product  of 
cinchonin,  and  secondly,  the  isomeric  base,  a-i-cinchonin.  The  first 
reaction  or  product  acts  in  some  way  as  the  catalyzer  for  the  second 
reaction,  the  transformation  into  the  isomeric  base.  It  is  certain  that 
the  concentration  of  the  hydrogen  ions  does  not  determine  the  velocity 
of  the  formation  of  the  isomeric  base.  The  accelerating  influence  of 
the  side  reaction  of  addition  upon  the  reaction  of  transformation  may 
be  regarded  as  one  of  two  procedures.  Either  some  intermediary 
stage  of  the  addition-reaction    constitutes  an  intermediary  stage  of 


100  THE  THEORY  OF  FERMENT  ACTION 

the  transformation-reaction,  i.  e.,  in  the  series  of  intermediary  stages 
of  the  addition-reaction  is  a  point  where  the  process  may  go  on  to 
the  reaction  of  transformation,  a  point  where  the  line  of  least  chemical 
resistance  lies  in  the  direction  of  the  transformation -reaction;  or  the 
two  lines  of  direction  are  early  separated  and  some  product  of  the 
addition-reaction  acts  as  a  catalyzer  to  the  transformation-reaction 
and  produces  with  this  reaction  intermediary  states  that  carry  with 
them  a  heightened  velocity  of  this  second  reaction.  Most  probably 
the  first  reaction  alone,  the  addition-reaction,  is  an  auto-reaction;  the 
second  reaction  is  not  one  that  exists  per  se  and  is  simply  accelerated 
by  the  first  reaction,  the  first  reaction  or  its  products  actually  calls 
the  second  reaction  into  being. 

We  meet  here  with  an  apparent  contradiction  of  the  statement  that 
a  fermentation  is  an  acceleration  of  an  already  existing  reaction.  If 
in  a  catalysis  or  fermentation  the  end  product  is  different  than  that 
yielded  in  the  un accelerated  reaction,  the  relations  suggest  a  reaction 
de  novo.  When  the  relations  are  carefully  scrutinized,  however,  it 
seems  clear  that  we  are  dealing  not  with  a  contradiction,  but  with  an 
extension  of  the  principle.  Even  though  in  some  instances  the  end 
product  be  different  in  the  accelerated  and  unaccelerated  reactions, 
it  is  the  existence  of  the  primary  unaccelerated  reaction  that  makes 
possible  the  secondary  reactions  in  the  process  of  acceleration  that 
yields  the  end  products.  In  the  domain  of  organic  substances  lability 
is  so  great  and  the  possibilities  of  reactions  so  numerous  that  many 
possibilities  for  the  installation  of  side  reactions  are  presented  in  the 
catalyses  and  fermentations  of  such  substances.  This  may  be  illus- 
trated in  the  following  scheme: 

Substrate  +  water  — +  pa  — *  pb  — *  pc  — *  end  product  A  (auto-reaction) 
Substrate  +  water  +  ferment 

— >  pr  —>  Pa  — >  pt  — >  Pu  — >  end  product  A  (accelerated  reaction) 
- > py  — >  pz  — ►  end  product  B  (side  reaction) 

Obviously  the  side  reaction  is  not  a  reaction  de  novo,  but  is  as  essen- 
tially an  acceleration  (and  deviation)  of  the  auto-reaction  as  is  the 
accelerated  reaction  that  yields  the  same  end  product  as  the  auto- 
reaction.  And  were  the  entire  trend  of  the  reaction  to  take  the  side 
path  and  product  B  appear  as  the  sole  end  product,  that  fact  would 
hold  just  as  true.  In  many  of  the  cases  we  are  dealing  with  incompleted 
or  superimposed  reactions.  Thus  sugar  may  apparently  be  fermented 
to  alcohol  and  to  acetic  and  lactic  acid.  Now  there  can  be  little  doubt 
that  the  lactic  acid  fermentation  consists  in  the  reaction  as  described 
for  alcoholic  fermentation  checked  at  the  stage  of  lactic  acid;  and  the 
acetic  acid  fermentation  is  an  oxidation  fermentation  of  alcohol.  Up 
to  the  present,  therefore,  we  have  no  data  tending  to  indicate  that 
natural  fermentations  are  ever  reactions  de  novo. 

In  organic  reactions  intermediary  products  have  been  less  often 
demonstrated,  on  account  of  the  greater  complexity  of  the  relations. 


THE  MODUS  OPERANDI  OF  FERMENTATION  101 

Some  are,  however,  known.  The  first  demonstrated  instance  (which 
is  now  known  to  be  susceptible  of  marked  catalytic  acceleration)  was 
contained  in  the  formation  of  ether  from  alcohol  through  the  action 
of  sulphuric  acid,  ether-sulphuric  acid  being  shown  to  represent  the 
intermediary  stage. 

H2S04  +  C2H5.OH  =  (C2H5)H  S04  +  H20 
(C2H5)H  S04  +  C2H5.OH  =  (C2H6)20  +  H2S04 

When  propyl  alcohol  is  heated  with  sulphuric  acid,  a  molecule  of 
water  is  withdrawn;  thereupon  another  molecule  of  water  is  added, 
though  in  a  different  way,  so  that  isopropyl  alcohol  is  formed. 

CH3.CH2.CH2OH  -  H20  =  CH3.CH  :  CH2  (propylen) 
CH3.CH  :  CH2  +  H20  =  CH3.CHOH.CH3  (isopropyl  alcohol) 

The  formation  of  acrolein  from  glycerol  by  heating  is  illustrated 
in  the  following  series: 

Glycerol  Acrolein  hydrate  Acrolein 

CH2 .  OH  CH2  CH2  CH2 

CH.OH  -  2H20  =  C  +  H20  =  CH  -  H20  =  CH 


CH2.OH  CH.OH  CH.(OH)2  C 


H.O 


According  to  the  now  accepted  theory,  when  water  and  carbon  dioxid 
are  in  contact  in  the  presence  of  sunlight  formaldehyd  is  slowly  formed, 
and  the  acceleration  of  this  reaction  is  assumed  to  constitute  the  first 
step  in  the  assimilation  of  carbon  by  plants.  The  reaction  may  be 
regarded  as  passing  through  the  intermediary  stage  of  formic  acid. 

H20  +  C02  -  H.COOH  +  O 
H.COOH  =  H.COH  +  0 

An  interesting  catalytic  intramolecular  transformation  affords 
another  good  illustration.  The  ketone  of  C5C160  presents  several 
isomers,  and  two  of  these  in  particular  tend  always  to  pass  into  each 
other  and  to  establish  an  equilibrium  in  the  mass.  The  reaction  is 
apparently  not  direct,  and  although  the  intermediary  body  has  not 
been  isolated,  the  evidence  seems  to  indicate  that  the  reaction  follows 
the  following  equation: 


C1C CC12  C12C 


CICl      JCCI2  C12C 


\ 


C  Cl2  ci  c 


CC12  C12C       Icci 


CC1 


CO 


(<o  Vo 


An  additional  illustration  is  furnished  in  the  equations  for  the  fer- 
mentation of  d-glucose  to  alcohol  and  carbon  dioxid.     There  the  one 


102  THE  THEORY  OF  FERMENT  ACTION 

certain  intermediary  product  is  lactic  acid,  which  has  been  confirmed; 
while  none  other  is  certainly  known,  a  methyl-glyoxylic  body  seems 
recently  to  have  been  identified  in  the  intermediary  series. 

Apart  from  the  considerations  adduced  for  alcoholic  fermentation 
(and  for  the  oxydases  and  peroxydases)  there  have  been  few  studies  of 
fermentations  from  the  point  of  view  of  intermediary  reactions.  As 
a  rule,  the  conditions  are  so  complex  and  uncontrollable  that  we  do 
well  if  we  are  able  to  estimate  the  march  of  the  reaction  and  the  nature 
of  the  final  products,  without  even  attempting  the  isolation  of  inter- 
mediary stages.  In  the  fermentations  of  the  hexoses,  in  the  platinic 
accelerations  of  cleavages  of  carbohydrates,  and  in  the  reactions  of 
hydrogen  peroxid  with  organic  bodies  the  relations  promise  soon  to 
be  sufficiently  clear  to  permit  of  investigations  from  this  point  of  view. 
We  know  that  ferments  are  very  labile  bodies,  that  precisely  such 
labile  bodies  have  the  tendency  to  enter  into  unstable  combinations, 
and  we  may  infer  that  in  this  very  quality  lies  their  adaptability  to 
the  acceleration  of  slow  reactions.  But  this  very  lability  makes  the 
intermediary  products  very  elusive  and  difficult  of  isolation,  so  that 
qualitative  results  are  probably  all  that  may  be  hoped  for  in  the  near 
future.  Schoenbein  spoke  of  the  reactions  of  hydrogen  peroxid  as 
the  "Urbild  aller  Gaehrung,"  and  this  terse  sentence  is  yearly  becom- 
ing more  impressive.  There  was  a  time  when  the  reactions  of  hydrogen 
peroxid  were  as  little  understood  as  are  those  of  the  common  ferments 
today;  and  it  is  not  too  much  to  hope  that  as  much  progress  may  be 
made  with  the  latter  within  the  next  decade  as  has  been  made  during 
the  last  three  decades  upon  the  study  of  the  catalyses  with  hydrogen 
peroxid. 

Although  we  are  not  as  yet  able  in  concrete  instances  of  fermentation, 
apart  from  alcoholic  fermentation,  to  point  out  the  intermediary  reac- 
tions, we  have  an  indirect  argument  for  this  theory  in  the  fact  that 
the  ferment  is  known  to  combine  with  the  substrate.  While  it  is  true 
in  the  general  sense  that  the  action  of  catalyzers  is  peculiar  in  this, 
that  there  is  no  stoicheiometric  relation  between  the  catalyzer  and  the 
substrate,  it  is,  on  the  other  hand,  equally  true  that  on  the  theory  of 
intermediary  reactions,  during  the  moment  of  reaction  there  must 
be  a  stoicheiometric  relation  between  them.  The  statement  that  there 
is  no  stoicheiometric  relation  between  the  catalyzer  and  the  reaction  it 
accelerates  is  true  only  in  the  relative  sense  that  there  is  no  stoicheio- 
metric relation  between  the  mass  of  the  catalyzer  and  the  mass  of 
initial  substrate  or  the  final  products.  But  so  long  as  we  locate  the 
modus  operandi  of  catalytic  acceleration  in  intermediary  reactions, 
there  must  obviously  be  a  stoicheiometric  relation  between  the  catalyzer 
and  the  substrate  in  the  moment  of  reaction.  This  is  as  true  of  colloidal 
platinum  as  it  is  of  ferrous  sulphate.  It  is  the  rapidity  of  the  inter- 
mediary reactions,  the  putting-on  and  casting-off  of  the  reaction,  so  to 
speak,  that  gives  the  gross  appearance  of  absence  of  a  stoicheiometric 
relation.    Only  on  such  a  basis  can  the  relation  of  degree  of  accelera- 


THE  MODUS  OPERANDI  OF  FERMENTATION  103 

tion  to  mass  of  catalyzer  or  ferment  be  explained.  It  is  most  probable 
that  when  the  common  fermentations,  the  reactions  of  monomolec- 
ular  order,  are  carefully  studied,  it  will  be  found  that  in  all  the  velocity 
of  acceleration  is  proportional  to  the  mass  of  the  ferment.  This  is 
just  what  we  should  expect,  since  the  only  relations  in  the  reactions 
are  the  masses  of  the  substrate  and  the  ferment.  It  might  be  assumed 
that  the  molecules  of  ferment  /  each  combined  with  one  of  substrate 
s.  This  would  give  us  /  +  s  =  fs  =  intermediary  product  (one  or 
more)  =  end  product  +  /.  This  /  would  then  combine  with  another 
molecule  of  substrate,  and  the  process  be  repeated.  On  the  basis  of 
this  scheme,  the  degree  of  acceleration  would  naturally  be  proportional 
to  the  number  of  /,  at  least,  within  certain  limits  of  relations  of  con- 
centration. 

There  have  been  several  other  considerations  urged  to  explain  the 
accelerations  of  catalysis  and  fermentation.  These  theories  do  not 
exclude  the  proposition  of  intermediary  reactions.  The  theory  of 
ionization  has  been  applied  to  this  entire  group  of  reactions.  This 
hypothesis,  though  unsupported  by  much  experimental  evidence,  is 
founded  upon  solid  general  considerations  and  regards  the  action  of  the 
catalyzer  as  a  positive  influence  on  the  magnitude  of  ionization  of  the 
reacting  bodies.  The  presence  of  the  reacting  body  is  considered  to  so 
alter  the  concentration  of  the  active  ions  that  the  reaction  is  hastened. 
"Chemical  catalyses  depend  upon  alterations  in  the  concentrations 
of  one  or  more  of  the  molecules  that  carry  on  the  unaccelerated 
reaction,  i.  e.  (by  the  application  of  the  electro-chemical  principle 
to  the  general  field  of  chemistry),  upon  an  increase  (or  a  decrease) 
of  the  ions  that  participate  in  the  reaction/'    (Euler.) 

But,  it  cannot  be  believed  that  this  alone  can  explain  catalysis  or 
fermentation,  independent  of  the  existence  of  intermediary  reactions. 

The  views  drawn  from  the  studies  of  the  catalytic  action  of  colloidal 
suspensions  of  metals  have  tended  to  exaggerate  the  physical  aspect 
of  the  subject.  Granting  unreservedly  the  accessory  influences  that 
the  physical  properties  of  colloidal  suspensions  (their  enormous  surface 
tension,  etc.)  may  possess  upon  a  reacting  system,  the  fact  remains 
that  the  catalytic  influence  of  colloidal  metals  must,  too,  be  attributed 
to  intermediary  reactions.  The  colloidal  state  must  be  held  to  endow 
the  metal  with  activity  in  the  chemical  sense,  to  activate  it  in  the  mass 
sense.  A  gross  suggestion  of  such  a  process  is  contained  in  the  proposi- 
tion that  if  a  metal  were  chemically  active  in  itself,  the  finer  the  sub- 
division of  the  metal  in  the  system,  the  greater  the  surface  exposed 
for  contact.  Thus  copper  and  platinum  are  slightly  catalytic  in  sheet 
form,  enormously  active  in  colloidal  state.  Whatever  the  process 
may  be,  we  may  be  sure  that  the  catalytic  property  of  colloidal  suspen- 
sions lies  in  the  chemical  activity  of  the  substance  in  that  state.  The 
physical  properties  of  colloids,  especially  of  the  stable  organic  colloids, 
are  indeed  difficult  of  definition  and  characterization,  and  almost 
impossible   of   control;   but   that    is   no    reason    why  the   "colloidal 


104  THE  THEORY  OF  FERMENT  ACTION 

properties"  should  be  blindly  invoked  as  an  explanation  of  whatever 
may  appear  obscure.  The  fundamental  fact  in  the  phenomenon  of 
fermentation  is  a  chemical  act;  and  howsoever  the  physical  conditions 
of  the  reacting  substances  and  the  system  may  modify  that  reaction 
in  one  direction  or  another,  they  cannot  supplant  the  chemical  reaction 
as  the  fundamental  fact  of  the  phenomenon. 

Lastly,  the  specificity  of  enzyme  action  is  in  obviously  harmonious 
relation  to  the  theory  of  catalytic  acceleration  through  intermediary 
reactions.  In  a  word,  both  the  occurrence  of  the  fermentation  per  se 
and  the  specificity  of  this  action  are  founded  upon  intermediary  reactions. 

THE   SPECIFICITY   OF   FERMENT    ACTION 

In  many  text-books  on  physiology  one  meets  with  the  statement 
that  the  specific  limitations  of  the  power  of  ferments,  the  ability  to 
ferment  but  one  or  at  most  nearly  allied  bodies,  constitutes  a  distinc- 
tion between  ferments  and  inorganic  catalyzers.  This  statement  is 
incorrect.  There  are  many  instances  of  quite  specific  action  among 
inorganic  catalyzers.  For  example,  iron  salts  act  as  good  catalyzers 
for  the  oxidation  of  potassium  iodide  by  a  persulphate;  but  they  will 
not  accelerate  the  reaction  of  the  same  persulphate  upon  sulphurous 
acid.  Wolf  ramie  acid  is  an  active  catalyzer  for  the  oxidation  of  hydri- 
odic  acid  by  hydrogen  peroxid,  but  it  will  not  accelerate  the  same 
oxidation  by  a  persulphate.  Platinum  black  is  a  good  accelerator 
for  the  hydrolysis  of  esters  of  the  simple  alcohols,  but  it  has  no  ap- 
preciable effect  upon  the  hydrolysis  of  esters  of  glycerol.  Laccase 
will  accelerate  the  oxidation  of  many  aromatic  bodies,  and  the  re- 
duction ferments  will  accelerate  many  different  reactions  of  reduc- 
tion. A  simple  contemplation  of  the  chemical  relations  concerned 
leads  to  the  view  that  since  these  accelerations  are  to  be  regarded 
as  founded  upon  intermediary  reactions,  whether  a  catalyzer  or  ferment 
acts  or  not  will  depend  solely  upon  the  particular  reaction  involved. 
The  dissociated  hydrogen  ions  are  indeed  quite  general  catalyzers 
for  reactions,  but  they  do  not  share  this  generality  of  action  with  many 
inorganic  catalyzers.  An  interesting  exception  to  the  rule  that  hydrogen 
ions  act  as  general  catalyzers  of  hydrolyses  is  found  in  the  observation 
that  acids  are  not  able  to  convert  adenin  and  guanin  into  xanthin 
and  hypoxanthin,  though  these  are  reactions  of  hydrolysis.  All  cata- 
lyzers may  be  said  to  be  more  or  less  specific;  the  inorganic  catalyzers 
are  less  specific  (i.  e.,  have  a  wider  range  of  availability  in  the  inau- 
guration of  intermediary  reactions)  than  the  organic  ferments.  The 
specificity  itself  must  theoretically  be  vested  in  the  chemical  relations 
of  the  intermediary  reactions. 

In  a  discussion  of  the  specificity  of  ferment  action  we  must  distinguish 
between  quantitative  and  qualitative  specificity.  By  quantitative 
specificity  we  mean  whether  a  ferment  does  or  does  not  accelerate  a 
certain  reaction.     By  qualitative  specificity  we  mean  that  a  ferment 


THE  SPECIFICITY  OF  FERMENT  ACTION  105 

not  only  accelerates  a  reaction,  but  so  modifies  it  as  to  determine  the 
chemical  nature  of  the  products. 

In  the  beginning  it  must  be  pointed  out  that  the  fermentability  of 
a  certain  body  is  only  a  relative  term  with  a  time  limitation.  When 
we  say  that  a  certain  ferment  will  not  act  upon  a  certain  substance, 
we  usually  mean  that  a  test  of  several  hours  or  days  is  made  and  the 
results  then  determined  with  a  certain  analytical  precision.  The 
accuracy  of  the  observation  depends  upon  the  purity  of  the  reacting 
bodies,  the  stability  of  the  ferment,  the  length  of  time  permitted,  and 
the  delicacy  of  the  analytical  procedures  used  to  determine  the  occur- 
rence of  the  reaction.  It  is  apparent  that  a  ferment  could  act  in  a 
positive  manner,  but  that  the  acceleration  might  not  be  measurable 
under  the  chosen  or  necessary  conditions  of  the  experiment.  In  a 
strict  sense  one  ought  to  demonstrate  that  the  velocity  of  the  reaction 
with  the  ferment  of  supposed  inactivity  is  identical  with  the  velocity 
in  the  simple  system  without  ferment.  For  example,  pentoses  are 
not  fermentable  with  zymase;  but  an  appreciable  quantity  of  alcohol 
and  carbon  dioxid  could  appear  in  such  an  experiment,  derived  from 
the  glycogen  contained  in  the  extract  of  the  yeast.  Reviewing  the 
reported  work  one  is  impressed  with  certain  facts:  As  a  rule,  the  time 
has  been  too  short;  the  analytical  methods  for  the  determination  of 
the  occurrence  of  a  reaction  have  often  been  crude;  and  the  reacting 
bodies  and  ferments  have  rarely  been  pure  enough  to  insure  an  un- 
equivocal interpretation  of  positive  or  negative  results.  If  the  successful 
reversions  of  ferment  action  had  been  done  in  the  routine  manner  of 
testing  for  ferment  action,  not  a  single  one  of  the  now  demonstrated 
reversions  would  have  been  demonstrated. 

Many  ferments  have  but  a  limited  range  of  activity;  they  are  able 
to  ferment  but  certain  few  substances.  When  we  say  tljat  a  ferment 
is  able  to  act  upon  a  certain  body,  we  mean  to  a  measurable  degree. 
For  example,  trypsin  is  able  to  ferment  protamin;  pepsin  is  not  able 
to  ferment  it.  By  this  we  mean  that  in  a  test  of  several  weeks  no 
demonstrable  quantity  of  arginin  may  be  recovered  from  the  system. 
For  many  other  ferments,  however,  the  situation  is  different,  in  that 
a  very  slow  fermentation  occurs.  Thus  pepsin  ferments  reticulin  with 
difficulty,  trypsin  with  still  greater  difficulty,  so  that  the  current  state- 
ment is  that  reticulin  cannot  be  fermented  with  trypsin.  In  all  prob- 
ability the  true  statement  would  be  that  outside  of  the  fermentations 
of  the  carbohydrates,  which  have  been  best  studied,  all  statements  of 
non-activity  applied  to  ferments  usually  mean  that  under  the  condi- 
tions of  the  experiment,  in  the  short  life  of  the  ferment,  no  appreciable 
reaction  occurred;  and  it  is  not  equivalent  to  the  physico-chemical 
statement  that  such  and  such  a  ferment  is  not  a  catalyzer  for  such  and 
such  a  reaction. 

In  the  case  of  the  sugars,  however,  the  experimental  data  are  much 
greater  in  amount,  and  of  good  quality.  The  fermentability  of  sugars 
rests  upon  their  own  stereoisomeric  configuration  and  upon  an  appro- 
priate assumed  stereoisomeric  configuration  upon  the  part  of  the  mole- 


10G  THE  THEORY  OF  FERMENT  ACTION 

cule  of  ferment.  Certain  yeasts  will  ferment  only  certain  sugars  and 
identical  results  are  obtained  with  powdered  yeast  cells  or  their  expressed 
juices.  To  make  the  experiments  convincing,  the  configuration  of  the 
sugars  under  study  must  be  undoubted,  and  to  fill  this  requirement 
one  employs  for  crucial  experiment  synthesized  sugars. 

The  fermentability  of  a  sugar  depends,  according  to  the  now  accepted 
hypothesis,  upon  the  stereoisomeric  configuration  of  its  own  molecule 
and  of  the  molecule  of  the  ferment.  Many  facts  in  the  chemistry  of 
the  sugars  indicate  that  the  resistance  to  reactions  and  the  reaction 
ability  is  allied  not  solely  to  the  structural,  but  also  to  the  stereo-isomeric 
configuration.  The  different  hexoses  present  widely  varying  relations 
to  the  different  compounds  of  hydrazin;  the  different  osazones  and 
hydrozones  vary  widely  in  their  solubility,  velocity  of  formation, 
stability,  crystal  properties,  etc.  The  resistance  of  different  sugars 
toward  simple  reagents  like  acids  display  also  variations.  Thus,  mal- 
tose is  most  easily  hydrolyzed  by  acid,  cane  sugar  next,  and  lactose 
most  difficult  of  all.  Two  molecules  of  d-glucose  unite  to  form  a 
disaccharid,  maltose;  but  two  molecules  of  d-levulose  or  of  d-galactose 
do  not  unite  to  form  disaccharid,  though  each  of  them  will  unite  with 
d-glucose  to  form  disaccharids,  they  do  not  unite  with  each  other. 
From  the  point  of  view  of  fermentations  as  accelerations  through 
intermediary  reactions,  the  hypothesis  is  very  feasible,  since  the  con- 
figuration might  naturally  be  supposed  to  be  of  dominating  influence 
in  such  intermediary  reactions.  The  specificity  of  the  ferment  lies 
in  the  coadaptation  of  the  configuration  of  a  particular  ferment  to 
certain  sugars. 

For  the  members  of  the  benzol  series  a  large  number  of  instances 
are  known  in  which  reaction  affinity  is  dependent  upon  or  associated 
with  a  certain  configuration.  The  location  of  radicals  in  a  benzene 
ring  determines  often  the  resistance  to  chemical  reaction  displayed 
by  that  body,  in  that  the  substitution  of  hydrogen  is  not  effected  with 
the  same  readiness  when  the  radicals  occupy  different  positions.  Thus 
substitution  by  sulphur  radicals  is  easy  in  meta-xylol,  less  ready  in 
ortho-xylol,  and  difficult  in  para-xylol.  In  the  case  of  substitution  by 
nitric  acid  on  the  contrary,  as  for  instance  in  the  action  of  nitric  acid 
upon  the  isomeric  nitrotoluols,  the  reaction  is  most  easy  in  ortho- 
and  most  difficult  in  meta-nitrotoluol.  The  oxidation  of  a  lateral 
chain  to  a  carboxyl  group  is  likewise  related  to  the  configuration; 
ortho  derivatives  resist  the  action  of  chromic  acid  entirely,  while  para 
derivatives  are  quite  susceptible;  thus  ortho-brom-benzylbromid  is 
entirely  refractory  to  chromic  acid,  while  the  para-brom-benzyl-bromid 
is  easily  oxidized.  Salicylic  acid  is  a  much  stronger  acid  than  the  para- 
or  meta-oxybenzoic  acid.  Para-  and  ortho-xylol  are  easily  oxidized, 
meta-xylol  only  with  difficulty.  Similar  relations  exist  for  the  splitting 
off  of  the  carboxyl  group;  in  ortho-  and  para-oxybenzoic  acid  this 
may  be  accomplished  by  hydrochloric  acid,  which  will,  however,  fail 
with  the  meta-oxybenzoic  acid.  In  the  case  of  the  chlorhydrates  of 
nitro-anilins,  the  dissociation  varies;    at    ordinary  temperature  the 


THE  SPECIFICITY  OF  FERMENT  ACTION  107 

ortho  derivative  is  dissociated  to  10  per  cent.,  the  para  to  5  per 
cent.,  and  the  meta  derivative  to  but  less  than  1  per  cent.  In  an 
analogous  manner,  the  catalytic  action  of  metals  in  synthetic  reac- 
tions with  aromatic  bodies  illustrates  a  certain  specificity;  thus  in 
the  sulphuring  of  anthrachinons  in  the  presence  of  the  salts  of  mer- 
cury, sulpho  acids  of  the  a  series  are  formed  in  large  part,  which  is 
not  true  in  the  presence  of  other  heavy  metals.  Another  illustration 
is  the  action  of  boric  acid  in  the  synthesis  of  poly-oxy-anthrachinons. 
Not  only  is  there  a  relation  of  specificity  between  the  configuration 
of  the  reacting  aromatic  body  and  the  metal,  there  is  also  a  specificity 
in  the  resulting  product,  and  in  a  general  sense  under  these  circum- 
stances these  metals  might  be  spoken  of  as  catalyzers  that  not  only 
accelerate  the  velocity  of  the  reaction  but  also  modify  the  products. 
Illustrations  may  be  adduced  from  the  chemistry  of  the  benzene  series 
in  which  the  interreaction  of  two  ring  compounds  is  dependent  upon 
an  appropriate  configuration  of  the  two  molecules. 

A  very  striking  illustration  of  the  relations  of  reaction  acceleration 
to  configuration  is  to  be  noted  in  the  recent  studies  in  photochemistry. 
The  sensibility  to  light  upon  the  part  of  aromatic  bodies  is  noted  only 
in  such  bodies  as  possess  a  nitro  group  in  the  ortho-  position  to  a  CH2 
group.  Now  many  of  these  bodies  are  fermentable,  and  the  fermenta- 
tive accelerations  bear  similar  relations  to  the  configuration.  Thus 
laccase  will  accelerate  the  oxidation  of  hydrochinon  (para-dioxybenzol), 
but  will  not  ferment  the  ortho-  (pyro-catechin)  or  the  meta-dioxybenzol 
(resorcin).  Tyrosinase,  furthermore,  will  ferment  metatoluidin,  but  not 
the  ortho-  or  para-toluidin,  while  it  will  ferment  all  three  of  the  xylenes. 

Other  suggestive  illustrations  of  the  relations  between  configuration 
and  reactionability  are  to  be  seen  in  the  esterfication  of  different 
benzoic  acids.  The  replacement  of  the  hydrogen  atoms  in  the  ring 
results  in  a  reduction  of  the  tendency  to  the  reaction  due  to  the  absence 
of  the  hydrogen,  which  accelerates  reaction.  The  measurement  of 
the  reaction  is  accomplished  by  introducing  the  benzoic  acids  into  an 
excess  of  methyl  alcohol  saturated  with  hydrochloric  acid.  But  the 
relations  of  the  different  hydrogens  are  not  identical.  The  carboxyl 
group  being  placed  in  the  position  of  1  in  the  ring,  if  the  hydrogens 
are  replaced  from  2  and  4,  or  from  3,  4,  and  5,  over  95  per  cent,  of 
ester  will  be  formed;  while  if  the  two  hydrogens  adjacent  to  the  carboxyl 
group  are  replaced,  at  2  and  6,  or  at  2,  4,  and  6,  almost  no  ester,  less 
than  5  per  cent.,  will  be  formed.  Of  influence  further  is  the  mass  of 
the  radicle  that  replaces  the  hydrogen  in  the  ortho  position  to  the 
carboxyl  group;  thus  bromin  and  iodin  with  their  heavy  molecular 
weights  depress  the  esterfication,  while  methyl  has  but  slight  inhibitory 
effect.  Fumaric  acid  does  not  tend  to  the  formation  of  the  anhydrid 
while  the  isomeric  maleic  acid  does  tend  to  the  formation  of  the 
anhydrid;  this  may  be  ascribed  to  the  fact  that  in  maleic  acid  the 
carboxyl  groups  are  adjacent,  while  in  fumaric  acid  they  are  separated. 
This  relation  of  the  tendency  to  anhydrid  formation  to  the  relative 
situations  of  the  carboxyl  groups  seems  to  hold  in  many  compounds. 


108  THE  THEORY  OF  FERMENT  ACTION 

Since  internal  configuration  of  the  molecule  is  of  such  striking  influ- 
ence on  reaction  properties,  this  will  apply  to  two  molecules  in  reaction. 
In  other  words,  that  which  is  true  of  the  substrate  must  hold  true  for 
the  ferment.  The  molecule  of  ferment  we  know  to  be  very  complex. 
That  it  has  the  same  relations  of  reaction  to  internal  configuration, 
we  cannot  doubt.  And  for  both  ferment  and  substrate,  the  reaction 
properties  may  lie  either  in  a  relation  of  the  configuration  to  the  internal 
resistance  or  to  the  factor  of  chemical  affinity;  for  the  acceleration  of 
the  reactions  of  the  substrate  by  the  ferment,  however,  we  must  hold 
that  the  specificity  of  the  ferment  lies  in  a  reduction  of  the  internal 
chemical  resistance  of  the  substrate  through  the  introduction  of  specific 
intermediary  reactions. 

Many  substances  present  in  addition  a  particular  form  of  variation 
in  the  intramolecular  configuration,  namely,  stereo-isomerism,  due  to 
the  presence  of  asymmetric  atoms  of  carbon.  The  sugars  are  such 
bodies,  also  the  amino-acids  found  in  proteins,  with  the  exception  of 
glycocoll.  The  ferments  are  protein-like  in  nature,  and  are  certainly 
stereo-isomeric. 

Among  the  reaction  possibilities  of  an  asymmetric  substance,  we 
might  most  reasonably  suppose  that  some  reaction  tendencies  as  well 
as  resistance  to  reaction  might  be  vested  in  the  stereo-isomeric  con- 
figuration, and  this  would  also  correspond  to  the  stereo-isomeric  con- 
figuration of  the  second  reacting  molecule.  This  relation  of  the  two 
reacting  molecules  Fischer  compared  to  the  relations  between  a  lock 
and  key;  and  as  a  purely  symbolic  illustration  he  compared  the  lateral 
recessions  of  the  lock  and  the  lateral  projections  of  the  key  to  the  lateral 
arrangements  of  the  elements  upon  the  carbon  chain  of  a  sugar  mole- 
cule. This  means  simply  a  correlation  favorable  to  interreaction  in 
the  purely  chemical  sense. 

Certain  configurations  endow  the  molecule  with  a  marked  resistance 
to  the  reaction;  the  ferment  modifies  this  internal  resistance. 

There  are  sixteen  possible  stereo-isomerids  of  hexose.  Of  these 
twelve  have  been  isolated  from  natural  sources  or  synthesized.  Of 
these  but  four  are  susceptible  of  alcoholic  fermentation  by  .zymase : 
d-glucose,  d-mannose,  d-levulose,  and  d-galactose.  For  purposes  of 
illustration,  the  stereo-isomeric  configurations  of  these  will  be  given, 
together  with  that  of  d-talose,  which  is  not  fermentable. 

d-glucose  d-mannose  d-fructose  d-galactose  d-talose 

COH  COH  CH2.OH  COH  COH 

H.C.OH         HO.C.H  CO  H.C.OH         HO.C.H 


I  1  I  I 

~  C.H  HO.C.H  HO.C.H  HO.C. 


HO.C.H  HO.C.H  HO.C.H  HO.C.H  HO.C.H 

H.C.OH  H.C.OH           H.C.OH  HO.C.H  HO.C.H 

I  I                          I  I  I 

H.C.OH  H.C.OH           H.C.OH  H.C.OH  H.C.OH 

CH2.OH  CH2.OH            CH2.OH  CH2.OH  CH2.OH 


THE  SPECIFICITY  OF  FERMENT  ACTION  109 

The  d-glucose,  d-levulose,  and  d-mannose  are  identical  in  this,  that 
the  relations  of  the  three  asymmetric  atoms  of  carbon  that  are  common 
to  them  all  are  alike.  The  other  asymmetric  atom  in  the  d-glucose 
and  d-mannose  seems  to  be  of  no  determinable  influence.  In  the  mole- 
cule of  the  d-galactose  there  is  the  difference  from*  the  other  three, 
that  in  the  centre  one  of  the  three  asymmetric  atoms  of  carbon  common 
to  them  all,  the  centre  carbon  has  the  relations  of  hydrogen  and  hydroxy  1 
reversed  laterally.  The  upper  asymmetric  carbon  is  identical  in  its 
relations  with  the  corresponding  atom  of  the  d-glucose,  but  has  the 
reverse  relation  of  lateral  attachments  possessed  by  the  d-mannose. 
Nevertheless,  these  differences  are  not  determinating,  since  d-galactose 
may  be  fermentable  by  the  same  yeasts,  though  some  yeasts  cannot 
ferment  it  at  all,  and  all  do  so  with  slower  velocity.  It  is,  therefore, 
not  the  situations  of  individual  hydroxyls  that  determine  the  ferment- 
ability,  but  the  total  combination.  Thus,  d-talose,  which  is  n  on  -ferment- 
able, resembles  d-mannose  in  the  relations  of  the  upper  asymmetric 
carbon,  d-galactose  in  the  relations  of  the  two  middle  asymmetric 
carbons,  and  all  four  in  the  relations  of  the  lower  asymmetric  carbon. 
A  direct  rule  is  obviously  not  contained  in  these  facts,  but  somewhere 
in  the  series  of  asymmetric  carbon  atoms  of  d-talose  is  a  high  passive 
resistance  not  encountered  in  the  others,  while  somewhere  in  the  series 
of  asymmetric  carbons  in  d-galactose  is  a  certain  degree  of  passive 
resistance  not  met  with  in  the  other  three.  There  can  be  no  doubt 
that  the  facts  suggest  a  quantitative  rather  than  a  qualitative  difference. 

It  has  been  suggested  that  the  fermentability  of  the  hexoses  lies  in 
their  being  convertible  into  d-glucose;  only  d-glucose  is  fermentable, 
and  those  sugars  only  subject  to  fermentation  that  are  convertible 
into  d-glucose.  That  these  hexoses  may  be  easily  converted  into  each 
other  through  the  action  of  alkali  has  been  shown.  The  formation  of 
d-levulose  from  d-glucose  is  according  to  recent  investigations  not 
confined  to  experimental  conditions  but  occurs  in  every  hydrolysis  of 
starch,  arising  not  from  the  starch  directly  but  by  derivation  from 
d-glucose. 

Clearer  relations  are  secured  in  the  fermentation  of  natural  and 
synthetic  glucosids.  When  aldo-hexoses  are  heated  in  alcoholic  hydro- 
chloric acid,  glucosids  are  formed.  Of  both  the  d-  and  1-sugars  two 
isomers  are  formed,  termed  the  a  and  b  series.  Thus  for  methyl  alcohol 
we  have  the  two  isomers  of  d-glucose : 

H.C.OCH3  CH3O.C.H 


H.CX>H^-^  H.C. 


OH 


110  THE  THEORY  OF  FERMENT  ACTION 

The  glucosids  of  the  1-series  of  glucose,  mannose,  and  galactose 
are  not  fermentable  at  all.  The  glucosids  of  the  d-series  of  glucose, 
mannose,  and  galactose  are  fermentable,  and  to  a  noteworthy  degree 
specifically.  The  a-glucosids  of  these  d-hexoses  are  fermentable  with 
yeast,  the  6-glucosids  are  fermentable  with  emulsin.  The  natural 
glucosids  are  6-glucosids,  so  that  the  concordance  between  the  natural 
and  the  synthetic  glucosids  is  complete.  It  is  not  the  zymase  in  the 
yeast  that  accelerates  these  reactions;  it  is  the  maltase.  The  data 
bearing  on  these  synthetic  glucosids  is  very  positive,  and  suggests 
strongly  the  validity  of  specificity. 

Very  instructive  is  the  study  of  the  try p tic  digestion  of  synthetic 
peptids.  Of  the  synthetic  peptids  that  have  been  prepared  many 
are  digestible  with  trypsin.  When  racemic  peptids  are  digested  with 
trypsin,  the  cleavage  is  an  asymmetric  one;  and  the  amino-acid  that 
is  split  off  is  the  same  active  amino-acid  that  is  to  be  found  among 
the  products  of  the  digestion  of  natural  protein  by  trypsin.  There 
are  two  racemic  alanyl-leucin  peptids,  and  they  include  the  four 
possible  combinations  of  the  two  components.  Thus,  alanyl-leucin  A 
is  d-alanyl-1-leucin  +  1-alanyl-d-leucin;  while  B  is  d-alanyl-d-leucin 
+  1-alanyl-l-leucin.  Only  A  is  digestible,  and  of  the  compound  only 
the  d-alanyl-1-leucin  is  split  off,  and  the  two  components  separated. 
These  facts  have  all  the  more  weight,  because  they  have  been  obtained 
with  a  class  of  compounds  totally  different  from  the  sugars. 

According  to  the  theory,  since  the  velocity  of  reaction  under  the 
influence  of  a  ferment  depends  upon  the  stereo-isomeric  configuration 
of  the  ferment  molecule,  the  influence  of  organic  acids  upon  the  same 
reactions  might  depend  upon  similar  relations.  But  when  cane  sugar 
is  hydrolized  by  d-  and  1-camphoric  acid,  the  acceleration  is  identical 
for  the  two,  i.  e.,  the  acceleration  depends  upon  the  electrolytic  dis- 
sociation, and  not  upon  the  optical  isomerism. 

Another  interesting  point  from  which  to  view  the  theory  lies  in  the 
fermentation  of  racemic  acids.  Both  the  d-  and  1-acids  are  fermented, 
but  with  different  velocities.  In  some  few  instances  the  reactions  upon 
the  two  enantiomorphic  bodies  are  quite  equal,  in  other  instances  there 
is  a  distinct  predominance;  in  a  few  instances  the  reaction  with  the 
one  is  marked,  with  the  other  very  slight.  The  greater  velocities  are 
in  the  direction  demanded  by  theory  of  specificity.  The  temperature 
optimum  is  different  for  the  d-  and  1-acids.  If  these  results  may  be 
applied  to  the  fermentation  of  sugars,  it  indicates  that  the  specificity 
may  be  only  one  of  degree;  not  a  question  of  reaction  or  no  reaction, 
but  of  slight  reaction  as  against  pronounced  reaction. 

Finally,  one  may  study  the  cleavage  of  optically  inactive  racemic 
synthetic  esters  by  lipase.  The  products  are  found  to  be  rotary  in 
one  direction,  and  the  residual  ester  is  rotary  in  the  opposite  direction. 
In  a  word,  the  cleavage  is  an  asymmetric  process.  But  it  is  only  a 
difference  in  velocity,  not  a  qualitative  differentiation.  The  fact  corre- 
sponding to  this  is  to  be  found  in  the  observation  that  two  optically 


THE  SPECIFICITY  OF  FERMENT  ACTION  111 

opposite  active  acids  do  not  form  ester  with  an  optically  active  alcohol 
with  the  same  velocity.  The  unequal  velocities  may  be  explained  as 
follows:  When  optical  isomers  combine  separately  with  the  same 
structurally  asymmetric  substance,  they  may  do  so  with  unequal 
velocities;  and  conversely,  the  products  formed  by  such  reactions, 
since  they  are  no  longer  optical  opposites,  might  be  expected  to  undergo 
further  changes  at  unequal  velocities.  If  the  enzyme  be  supposed  to 
be  dextrorotary  and  the  components  of  the  racemic  acid  be  represented 
by  -j-  S  and  —  S,  the  additive  compounds  formed  by  the  union  of  the 
ester  and  the  ferment  would  be  (+  e  +  S)  and  (+  e  —  S).  These 
two  compounds  are  obviously  not  enantiomorphic  (opposite  compounds 
would  be  respectively  ( —  e  —  S)  and  —  e  +  S),  and  might  therefore 
be  expected  to  be  formed  and  undergo  changes  at  different  velocities. 
Ferments  are  apparently  sometimes  active,  sometimes  racemic-sub- 
stances.  If  a  racemic  ferment  react  with  a  racemic  substrate,  we  would 
expect  the  formation  of  enantiomorphic  complexes  of  ferment-sub- 
strate, and  under  these  circumstances  we  should  expect  the  reaction 
relations  to  be  identical.  Obviously,  therefore,  we  should  expect  an 
active  acid  to  act  in  a  different  manner  from  a  racemic  or  an  inactive 
acid. 

The  reason  a  ferment  is  elective  must  be  ascribed  to  the  fact  that 
configuration  means  resistance  to  the  reaction  or  that  it  means  resist- 
ance to  the  catalyzer. 

The  question  of  qualitative  specificity  of  ferments  has  a  narrower 
interest,  though  it  is  one  of  importance.  Do  the  different  accelerators 
of  a  reaction  yield  the  same  products,  or  may  they  yield  different 
products?  It  is  obvious  that  with  a  pure  catalyzer,  a  body  that  simply 
diminishes  the  chemical  resistance  of  a  substance,  the  nature  of  the 
products  would  not  be  altered.  But  in  the  frequent  atypical  fermenta- 
tions, where  the  ferment  is  often  more  or  less  altered  in  the  course 
of  the  reaction,  some  alteration  in  the  products  might  be  expected. 
Such  alteration  might,  however,  not  always  be  properly  attributed  to 
the  catalytic  acceleration.  For  example,  a  certain  reaction  constitutes 
a  hydrolysis,  with  the  product  z.  The  ferment  enters  into  reactions 
with  z,  and  as  a  result  y  is  produced.  Here  we  have  a  new  reaction, 
one  not  connected  with  the  acceleration,  but  one  that  would  have 
occurred  were  we  to  mix  z  and  the  ferment.  The  reaction  constitutes 
a  new  reaction,  a  secondary  reaction  in  the  system.  An  illustration 
of  this  is  seen  in  the  transformation  previously  described  of  cinchonin 
into  the  isomeric  base,  a-i-cinchonin  under  the  action  of  hydrochloric 
acid.  The  product  slowly  adds  hydrochloric  acid;  this  is  a  secondary 
reaction  having  no  relation  to  the  accelerated  transformation  of  the 
cinchonin  into  the  isomer,  but  simply  a  reaction  between  the  a-i- 
cinchonin  and  HC1  such  as  would  occur  were  these  two  mixed  in  a 
solution.  A  further  possibility  lies  in  the  fact  that  the  products  may 
react  among  themselves  to  form  new  bodies,  which  are,  of  course,  not 
to  be  classed  as  products  of  the  fermentation.    For  example,  arginase 


112  THE  THEORY  OF  FERMENT  ACTION 

accelerates  the  hydrolysis  of  arginin  to  urea  and  ornithin.  The  fer- 
mentation proceeds  well  at  a  slightly  alkaline  reaction.  Now  the  alkali 
accelerates  the  hydrolysis  of  urea  to  carbon  dioxid  and  ammonia. 
The  appearance  of  ammonia  in  the  fermentation  of  arginin  by  arginase 
is,  therefore,  not  a  product  of  this  fermentation.  We  must  thus  bear 
in  mind  the  possibilities  of  secondary  reaction— reactions  between  the 
product  and  ferment,  between  product  and  solvent,  between  products 
and  some  extraneous  substance,  and  between  products  and  products. 
An  excellent  illustration  of  the  relations  to  an  extraneous  body  is 
furnished  by  experiments  on  the  chemical  fermentation  of  d-glucose. 
When  glucose  is  exposed  to  sunlight  in  the  presence  of  a  trace  of  sodium 
hydroxid,  ethyl  alcohol  is  produced;  when  calcium  hydroxid  is  employed 
lactic  acid  is  produced.  Now,  since  the  accelerator  is  the  hydroxyl  ion, 
which  is  the  same  in  each  system,  the  difference  in  product  must  be 
due  to  an  action  of  the  calcium  as  against  the  sodium.  It  is  clear, 
therefore,  that  only  under  conditions  of  experimentation  with  pure 
substances  can  we  determine  whether  different  ferments  produce 
different  products.  Practically  all  the  studies  in  connection  with  animal 
ferments  may  be  regarded  as  worthless  from  this  point  of  view. 

Now  theoretically  a  ferment  must  be  conceded  the  power  of  modify- 
ing the  reaction  that  it  accelerates,  of  accelerating  side  reactions  as 
well  as  direct  reactions.  There  are  undoubted  instances  in  which 
ferments  modify  the  course  of  the  reaction  in  the  qualitative  sense. 
The  illustrations  that  at  once  come  to  mind  are  the  different  results 
that  may  be  secured  with  fermentations  with  pure  cultures  of  micro- 
organisms under  different  conditions.  But  these  instances  cannot 
be  directly  quoted  in  a  chemical  discussion,  because  of  the  com- 
plexity of  the  relations.  We  have  definite  chemical  illustrations.  The 
hydrolysis  of  hydroxylamin  in  alkaline  solution  follows  the  equation: 
3  NH30  =  NH3  +  N2  +  3  H20,  while  the  acceleration  of  the  reaction 
with  platinum  follows  the  equation:  4 NH30  =  2  NH3  +  N20  +  3  H20. 
The  reactions  of  hydrazin  also  illustrate  the  modifications  that  may 
be  effected  by  other  relations  in  the  system.  Thus  in  simple  watery 
solution  the  reaction  with  platinum  runs:  2 N2H4  =  2  NH3  +  N2  +  H2. 
while  in  the  presence  of  an  alkali  the  reaction  is :  3  N2H4  =  2  NH3  + 
2  N2  +  3  H2.  Illustrations  also  are  to  be  observed  in  the  ferment  and 
acid  reversions.  When  lactase  is  allowed  to  act  upon  equal  parts  of 
d-glucose  and  d-galactose  a  disaccharid  is  formed;  this  is  not  lactose, 
as  would  be  expected  since  the  synthesis  is  the  ferment  reversion  of 
lactose  cleavage;  the  sugar  is  the  isomer  isolactose.  The  same  fact 
holds  true  for  the  synthesis  by  ferment  action  of  disaccharid  from 
d-glucose  by  maltase;  the  sugar  is  not  maltose,  but  the  isomer  iso- 
maltose.  These  modifications  are  best  explained  as  the  result  of 
qualitative  alteration  of  the  acceleration  by  the  ferment. 


CHAPTER    III 

DIGESTION 

The  functions  of  digestion  are  twofold:  the  conversion  of  large 
non-diffusible  molecules  into  small  diffusible  molecules,  and  the  cleavage 
of  complex  molecules  into  simple  bodies  in  order  that  these  may  be 
utilized  in  the  various  metabolic  processes  of  the  body.  To  pass  the 
wall  of  the  alimentary  tract  a  substance  must  be  diffusible.  The 
starches,  fats,  and  proteins  are  non-diffusible;  the  disaccharids  and 
primary  sugars,  that  are  constituents  of  a  natural  diet,  are,  however, 
diffusible.  On  digestion  the  starches  are  converted  into  the  component 
sugars,  which  are  diffusible.  Following  digestion  of  the  fat,  the  compo- 
nent parts,  glycerol  and  the  fatty  acids,  are  diffusible.  On  digestion 
of  the  protein  the  resulting  amido-acids  and  peptids  are  diffusible. 
It  is  immaterial  to  the  present  argument  whether  the  velocity  of  the 
processes  of  diffusion  of  these  several  substances  can  be  explained 
at  present  wholly  on  physical  grounds;  it  is,  however,  practically  a 
fact  that  a  non-diffusible  body  does  not  pass  the  wall  of  the  alimentary 
tract.  It  is  not  to  be  denied  that  under  certain  conditions,  a  colloid 
may  pass  the  intact  intestinal  wall;  but  this  does  not  occur  to  any 
demonstrable  extent  in  the  course  of  digestion.  The  second  function 
of  digestion  is  of  especial  importance  to  the  metabolism  of  protein. 
The  common  vegetable  fats  are  glycerids  of  the  same  fatty  acids  as 
exist  in  the  animal  body;  there  is  no  chemical  peculiarity  known  there. 
The  several  carbohydrates  of  the  diet  are  converted  in  the  body  into 
one  form  of  sugar,  d-glucose,  which  is  identical  with  the  sugar  of  the 
blood.  The  proteins  must  be  dismembered  in  order  that  the  body 
may  build  of  them  its  own  peculiar  proteins.  In  a  certain  sense, 
the  metabolic  acts  of  the  human  body  are  not  neo-constructions  but 
re-constructions;  and  for  these  re-constructions  it  is  necessary  that  the 
foods  be  reduced  to  simple  units.  These  units  are  relatively  small 
and  diffusible  substances,  and  from  them  the  body  builds  its  tissues. 
For  the  heating  of  the  body  the  same  general  truth  holds,  the  body 
does  not  burn  the  polysaccharid,  the  protein,  or  the  fat;  these  must 
first  be  split.  And  looking  at  the  matter  by  and  large,  the  forms  in 
which  these  are  available  for  the  combustions  of  the  body  are  identical 
with  the  states  in  which  they  are  absorbed  following  digestion  in  the 
alimentary  tract. 

From  a  contemplation  of  the  chemical  processes  that  occur  in  the 

cleavage  of  proteins,  carbohydrates,  and  fats  into  their  component 

bodies,  it  is  clear  that  digestion  is  a  reaction  of  hydrolysis.     All  the 

ferments  of  the  alimentary  tract  are  ferments  of  hydrolysis.     It  will 

8 


114  DIGESTION 

not  be  denied  that  enzymes  of  oxidation  or  reduction  occur  in  the 
juices  of  the  alimentary  tract  (though  such  have  never  been  properly 
demonstrated);  but  if  present  they  have  no  known  function  in  the 
reactions  of  digestion. 

Of  great  importance  in  the  physiology  and  pathology  of  digestion 
are  the  presence  and  metabolic  activities  of  bacteria.  The  relation 
of  abnormal  bacterial  infection  to  the  etiology  of  alimentary  disease 
requires  no  elucidation  here.  The  question  whether  bacteria  are 
physiologically  of  advantage  in  the  alimentary  tract  has  been  attacked 
by  direct  experiment.  The  guinea-pigs  that  were  first  brought  asep- 
tically  into  extra-uterine  life  and  kept  thus,  were  apparently  normal 
during  the  two  weeks  of  observation.  Later  experiments  on  fowl 
and  frogs,  extending  over  long  periods  of  time,  seem  to  have  shown 
that  growth  and  nutrition  are  not  normally  maintained  with  a  sterile 
alimentary  tract.  The  under-nourishment  of  the  animals  quickly  sub- 
sided when  bacteria  were  added  to  their  food.  The  function  of  bacteria 
in  this  connection  is  not  clear.  It  surely  does  not  lie  in  the  direction 
of  the  chemical  reactions  of  digestion.  It  is  possible  that  it  lies  in  the 
same  direction  as  the  freshness  of  foods,  so  necessary  to  proper  nutrition 
in  man,  in  the  sense  that  bacteria  elaborate  the  same  substances  that 
are  present  in  fresh  vegetables  and  fresh  meats.  The  whole  question 
is,  however,  in  such  a  state  of  obscurity  that  discussion  is  not  possible; 
it  is  only  necessary  to  mention  the  experimental  fact  that  normal 
nutrition  is  apparently  not  possible  with  a  sterile  alimentary  tract. 


DIGESTION   IN   VITRO 

Digestion  experiments  in  glass  present,  in  addition  to  obvious  con- 
veniences, the  direct  advantage  over  digestion  tests  in  a  stomach  or 
loop  of  intestine,  that  the  products  of  digestion  are  not  removed  from 
the  system  and  are  thus  available  for  analysis.  This  objection  does 
not  negate  gastric  tests  as  much  as  intestinal  experiments,  since  the 
processes  of  resorption  are  minimal  in  the  stomach  and  very  active 
in  the  intestine.  It  is,  however,  this  retention  of  the  products  of  diges- 
tion in  the  system  in  glass  that  is  responsible,  in  part  at  least,  for  the 
low  quantitative  yield  commonly  observed  in  such  tests.  The  accu- 
mulated products  of  the  reactions  check  the  action  of  the  ferments. 
It  can  be  shown  in  direct  experiment  in  the  digestion  of  synthetic 
peptids  with  trypsin  that  the  presence  of  amino-acids  checks  the 
digestion.  On  the  other  hand,  experiments  in  glass  are  at  a  disadvantage 
in  that  it  is  impossible  to  duplicate  in  the  test  all  the  natural  conditions 
that  surround  an  act  of  digestion.  The  psychic  concomitants  of  diges- 
tion are  of  great  influence  and  importance,  not  only  as  to  the  rate 
and  amount  of  the  secretion  of  the  juices  of  digestion,  but  also  as  to 
the  composition  of  the  juices  of  digestion.  To  procure  pure  juices  of 
the  digestive  glands,  we  must,  in  one  form  or  other,  practise  mock 


DIGESTION  IN  VITRO  115 

feeding;  and  there  is  no  question  that  juices  so  secured  cannot  be  held 
to  even  approximately  correspond  to  those  formed  and  operative  in 
normal  feeding  and  digestion.  There  are,  furthermore,  great  personal 
variations,  which  naturally  effect  the  results  in  tests  in  glass  more  than 
in  the  body.  Attempts  to  make  the  tests  in  the  animal  body  directly 
comparable  to  those  in  glass  by  preventing  resorption  (as  by  ligation 
of  the  orifices  of  the  stomach  and  of  its  bloodvessels)  are  totally  futile. 
On  the  whole,  we  may  say  that  the  results  of  experiments  in  glass  are 
qualitatively  comparable  to  those  in  the  body,  but  quantitatively  they 
are  very  defective. 

The  results  of  digestion  tests  in  glass  have  for  the  most  part  given 
direct  and  indubitable  results  for  the  fermentations  of  carbohydrates 
and  fats — in  which  the  results  were  of  lesser  importance.  In  the  case 
of  the  digestion  of  proteins,  which  is  of  the  greatest  practical  and  theo- 
retical importance,  it  has  taken  much  time  and  elaborate  experimenta- 
tion to  yield  data  that  are  adapted  to  the  solution  of  the  numerous 
physiological  problems  related  to  the  subject.  To  the  present  fairly 
satisfactory  state  of  knowledge,  the  study  of  the  digestion  of  synthetic 
peptids  has  contributed  greatly.  We  will  here  review  concisely  the 
fermentative  activities  of  the  different  enzymes,  leaving  the  discussion 
of  the  conditions  of  activity,  that  are  of  importance  to  an  understanding 
of  the  processes  of  digestion,  to  the  section  devoted  to  digestion  in  vivo. 

The  salivary  ferments  are  two,  amylase  and  maltase.  Amylase 
acts  to  accelerate  the  cleavage  of  starch  into  maltose,  the  reaction 
passing  throughout  various  stages  of  dextrins.  All  starches  are  sus- 
ceptible to  the  action  of  salivary  amylase;  the  different  degrees  of 
resistance  noted  experimentally  are  probably  due  more  to  differences 
in  methods  of  preparation  than  to  differences  in  origin  of  starches. 
Raw  starch  is  hydrolyzed  with  extreme  slowness.  After  the  poly- 
saccharid  is  converted  into  maltose  under  the  action  of  the  amylase, 
it  is  then  converted  rapidly  into  glucose  under  the  influence  of  the 
maltase.  The  two  ferments  are  entirely  distinct,  the  substrate  of  the 
reaction  of  the  maltase  is  the  product  of  the  reaction  of  the  amylase. 
Neither  ferment  has  any  qualitative  influence  on  the  sugars,  these 
are  simply  set  free,  as  they  existed  preformed,  by  the  reactions  of 
hydrolysis  accelerated  by  the  ferments  amylase  and  maltase. 

The  stomach  has  no  ferments  for  the  digestion  of  carbohydrate. 
In  the  secretion  of  the  pancreatic  juice  are  amylase  and  maltase,  that 
in  all  respects  compared  with  those  of  the  saliva.  The  juice  of  the 
pancreas  also  contains  lactase  but  no  invertase.  These  accelerate 
respectively  the  cleavage  of  the  disaccharids  cane  sugar  and  milk 
sugar,  into  their  component  hexoses.  All  the  four  ferments  are  con- 
tained in  the  succus  entericus,  which  in  all  known  ways  operate  precisely 
as  do  the  ferments  of  the  pancreatic  juice.  For  all  these  ferments  it 
is  known  that  they  are  able  to  accomplish  no  qualitative  changes  in 
the  sugars,  they  simply  set  free,  by  acceleration  of  the  reactions  of 
hydrolysis,  the  sugars  that  exist  preformed  in  the  disaccharids  and 


116  DIGESTION 

polysaccharids.  The  alimentary  tract  contains  no  enzymes  in  its 
secretions  that  ferment  or  act  in  any  way  upon  the  primary  sugars; 
the  simple  conversion  of  polysaccharids  and  disaccharids  into  primary 
sugars  is  the  full  chemical  function  of  amylase,  maltase,  invertase,  and 
lactase. 

The  gastric  secretion  contains  a  lipase.  When  this  is  allowed  to  act 
in  a  faintly  alkaline  reaction,  it  accelerates  the  cleavage  of  neutral 
fats,  and  of  the  complex  phosphatids,  into  glycerol  and  the  fatty  acids. 
The  pancreatic  juice  and  the  succus  entericus  contain  each  a  lipase, 
of  identical  properties.  That  these  juices  do  not  operate  very  well 
in  tests  in  glass  is  due  in  part  to  the  lack  of  zymo-excitors  contributed 
by  the  bile  in  intestinal  digestion.  These  ferments  in  no  way  modify 
the  chemical  nature  of  the  products  of  the  reaction  they  accelerate, 
they  simply  set  free  the  glycerol  and  fatty  acids  that  exist  preformed 
in  the  neutral  fats  and  phosphatids  whose  hydrolysis  they  accelerate. 
It  is  ferments  of  the  type  of  lipase,  amylase,  and  invertase  that  closely 
follow  in  their  manifestations  the  laws  known  to  exist  for  catalytic 
acceleration  in  general. 

Reverting  to  the  scheme  for  the  internal  constitution  of  the  protein 
molecule,  the  catalytic  activities  of  the  several  proteolytic  ferments 
may  be  briefly  stated.  It  is  easily  possible  that  future  studies  may 
radically  modify  our  present  conceptions. 

Pepsin. — Pepsin  digests  all  the  native  proteins  with  the  exception 
of  the  protamins.  It  splits  them,  however,  only  to  the  stage  of  the 
peptone.  It  cannot  cleave  peptones,  it  cannot  set  free  amino-acids. 
The  synthetic  peptids  are  not  split  by  pepsin.  So  far  as  is  to  be  seen, 
the  cleavage  of  protein  by  pepsin  is  exactly  like  that  of  acids  as  far 
as  the  stage  of  peptone.  Different  native  proteins  present  different 
degrees  of  resistance  to  pepsin.  Thus  keratin  is  very  resistant.  But 
differences  may  exist  even  between  nearly  related  proteins;  thus  serum 
globulin  is  much  more  difficult  of  digestion  by  pepsin  than  serum 
albumin.  Coagulation  increases  the  resistance  of  some  proteins  to 
peptic  digestion.    Dried  protein  is  very  resistant  to  digestion  by  pepsin. 

Trypsin. — The  secretion  of  the  pancreas  digests  nearly  all  native 
proteins,  including  the  protamins.  Collagen  and  reticulin  are 
refractory,  and  keratin,  native  serum  globulin,  and  egg  albumin  are 
very  resistant.  Coagulation  does  not  increase  the  resistance  of  proteins 
to  tryptic  digestion.  Peptones  are  easily  digested,  at  least  certain 
ones;  and  amino-acids,  especially  tyrosin,  appear  very  early  in  the 
course  of  a  tryptic  digestion,  at  a  time  when  the  larger  portion  of  the 
mass  is  still  in  the  stage  of  proteose.  The  digestion  of  protein  by  trypsin 
goes  completely  to  the  stage  of  polypeptids.  Beyond  this,  while  many 
polypeptids  are  completely  digested,  others  are  refractory;  these  have 
proceeded  from  what  used  to  be  called  the  antipeptone  that  has 
long  been  known  for  its  resistance  to  trypsin.  The  fraction  of  poly- 
peptid  that  resists  tryptic  digestion  varies  with  different  proteins, 
ranging  from  20  to  40  per  cent,  of  the  whole.    This  fraction  itself  is, 


DIGESTION  IN  VITRO  117 

however,  not  a  unit,  but  consists  of  two  parts,  one  relatively  and  the 
other  absolutely  resistant.  One  may  digest  a  protein  a  week  with 
trypsin,  and  at  the  end  of  this  time  find  50  per  cent,  of  the  nitrogen 
in  the  form  of  polypeptid.  If  this  digestion  be  prolonged  for  several 
months,  it  will  be  found  that  this  will  be  reduced  to  a  fifth  or  tenth 
of  the  total,  but  beyond  this  point  no  further  digestion  can  be  accom- 
plished. These  antipolypeptids  are  different  for  different  native  pro- 
teins; but  when  split  by  treatment  with  strong  acid,  they  yield  in 
particular  glycocoll,  prolin,  and  phenylalanin,  usually  with  glutamic 
and  aspartic  acids,  lysin,  and  arginin.     (Cf.  page  47.) 

A  tryptic  digestion  that  is  preceded  by  a  peptic  digestion  seems  to 
yield  in  part  different  results  than  those  observed  in  a  direct  digestion. 
If  a  preliminary  digestion  with  pepsin  has  preceded  the  action  of  trypsin, 
some  of  the  amino-acids  that  are  not  set  free  in  a  direct  tryptic  diges- 
tion will  be  set  free  in  part.  There  will  be  more  tryptophan,  glutamic 
acid,  lysin,  and  arginin  set  free;  and  of  the  total  content  of  prolin, 
which  is  not  set  free  at  all  in  a  direct  digestion,  some  will  be  found 
free.  The  difference,  however,  is  largely  a  quantitative  one.  Evidently 
the  pepsin,  that  in  itself  cannot  digest  peptones,  in  some  way  modifies 
some  of  them  so  as  to  afford  to  trypsin  an  entrance  into  groups  that 
otherwise  are  refractory  to  it. 

Trypsin  digests  many  synthetic  peptids.  The  relations  are  very 
complex.  The  cleavage  is  asymmetric.  Such  peptids  as  are  split 
by  trypsin  always  contain  the  two  or  more  components  of  the  same 
stereoisomeric  configuration  in  which  they  exist  naturally;  if  one  or 
more  of  the  component  amino-acids  presents  a  stereoisomeric  configura- 
tion that  is  not  to  be  found  in  a  naturally  existing  amino-acids,  the 
peptid  will  not  be  split.  But  the  converse  does  not  hold;  peptids 
composed  only  of  amino-acids  present  in  the  stereoisomeric  configura- 
tion seen  in  natural  amino-acids  are  not  all  digestible  by  trypsin,  some 
of  them  are  digestible,  others  are  not.  Another  fact  in  this  connection 
indicates  that  analogous  relations  hold  in  the  digestion  of  native  pro- 
teins by  trypsin.  It  is  possible  to  racemizate  asymmetric  amino-acids 
within  the  protein  molecule  by  the  action  of  alkali,  in  fact,  the  con- 
version of  the  d-  or  1-  form  into  the  racemic  state  occurs  more  easily 
when  the  amino-acids  are  bound  in  protein  than  when  free.  Proteins 
in  which  the  amino-acids  have  undergone  racemization  are  either 
resistant  or  entirely  refractory  to  tryptic  digestion. 

Trypsin  can  only  split  the  peptid  binding;  it  cannot  split  the  two 
molecules  of  amino-thio-propionic  acid  that  form  cystin,  it  cannot 
split  arginin  into  ornithin  and  urea.  Neither  can  it  split  the  analogous 
binding  of  glycocoll  to  benzoic  acid  in  hippuric  acid. 

Erepsin. — This  proteolytic  ferment  is  secreted  in  the  succus  entericus. 
It  is  inactive  upon  native  protein,  though  casein  and  the  histones 
are  slowly  digested,  protamin  also.  It  is  very  active  in  the  accelera- 
tion of  the  cleavage  of  peptones.  These  it  can  split  to  the  component 
amino-acids,  though  the  antipolypeptid  that  is  so  resistant  to  trypsin 


118  DIGESTION 

presents  difficulties  here  also.  The  amino-acids  of  the  resistant  poly- 
peptid  that  are  set  free  in  an  acid  hydrolysis  are  also  set  free  by  erepsin. 
The  activity  of  erepsin  is  as  well  displayed  on  the  products  of  a  peptic 
digestion  as  on  the  products  of  a  tryptic  digestion;  in  the  latter  case 
the  cleavage  of  the  peptids  is  completed  most  rapidly  in  the  case  of 
a  preliminary  peptic  digestion.  In  the  superimposition  of  the  action 
of  the  two  ferments  pepsin-erepsin,  trypsin-erepsin,  we  have  a  mechan- 
ism by  which  proteins  are  broken  into  their  component  amino-acids. 
Erepsin  digests  the  same  synthetic  peptids  that  are  digestible  by 
trypsin.    Like  trypsin  it  cannot  split  cystin,  arginin,  or  hippuric  acid. 

Pepsin  and  trypsin  split  all  the  conjugated  proteins,  erepsin  does  not. 
Once  split,  the  protein  portion  is  digested,  and  the  conjugated  protein 
is  thus  destroyed,  not  to  be  recovered  in  the  resorbed  products. 

None  of  the  proteolytic  ferments  modify  in  any  way  the  amino- 
acids  of  the  proteins  they  hydrolyze;  these  exist  in  the  digestion  products 
as  they  existed  preformed  in  the  molecule  of  protein. 

DIGESTION  IN   VIVO 

A  discussion  of  the  derivation  of  the  ferments  and  of  the  modus 
operandi  of  their  secretion  from  the  glands  in  which  they  were  formed 
does  not  lie  within  the  scope  of  the  present  treatise.  The  formation 
of  the  ferment  is  an  act  of  organic  synthesis,  a  problem  of  organic 
chemistry.  The  ferments  are  currently  regarded  as  highly  specialized 
proteins.  This  assumption  is  based  upon  the  facts  that  they,  in  the 
purest  state  in  which  they  have  thus  far  been  isolated,  give  the  common 
test  for  protein,  respond  to  many  of  the  group  tests  for  known  amido- 
acids,  on  cleavage  yield  amido-acids,  and  contain  about  the  same 
percentages  of  nitrogen  and  carbon  as  the  well-known  proteins.  It 
must,  however,  be  noted  that  the  more  preparations  of  ferments  are 
purified  the  less  definite  become  these  tests.  It  is  furthermore  proper 
to  state  that  the  analytical  data  at  our  disposal  is  not  in  disaccord 
with  the  idea  that  the  ferments  may  be  closely  associated  with  proteins 
in  the  form  of  complex  chemical  combinations  or  of  adsorption  com- 
pounds; that  of  a  preparation  commonly  termed  a  "ferment"  the 
larger  fraction  may  be  protein  and  the  real  ferment  present  only  as  a 
trace,  the  actual  chemical  nature  of  the  ferment  itself  being  unknown. 
In  our  consideration  of  the  processes  of  digestion,  however,  we  accept 
the  digestive  ferments  as  organic  substances,  probably  proteins  formed 
by  synthesis  from  the  common  proteins  of  the  blood,  and  having 
the  property  of  a  catalytic  substance  in  relation  to  the  reactions 
of  the  hydrolysis  of  carbohydrates,  proteins,  and  fats.  Present  in  the 
contents  of  the  digestive  tract  are  oxidation  and  reduction  ferments; 
since  these  reactions  have,  so  far  as  known,  no  integral  part  in  the 
processes  of  digestion,  they  can  receive  no  consideration  here.  It  is 
not  to  be  understood  from  this  that  the  possibility  of  reactions  of 
oxidation  and  reduction  being  present  as  intermediary  stages  in  the 


SALIVARY  DIGESTION  119 

hydrolysis  of  the  carbohydrates,  fats,  and  proteins  is  to  be  denied; 
quite  to  the  contrary.  But  we  have  no  data  bearing  upon  such  an 
aspect  of  the  subject. 

The  secretion  of  the  ferments,  the  process  by  which  the  formed 
ferment  is  discharged  from  the  glandular  cells  through  their  lining 
membranes  into  the  alimentary  tract,  is  a  physico-chemical  problem. 
For  the  purposes  of  the  present  treatise  the  problem  begins  when  the 
food  meets  the  digestive  juices  in  the  lumen  of  the  alimentary  tract. 

SALIVARY   DIGESTION 

The  secretions  of  the  salivary  glands  contain  ferments  of  one  type 
only  (apart  from  oxydases) — such  as  act  upon  carbohydrates.  It  is 
the  current  teaching  that  these  ferments  are  secreted  by  the  parotid 
and  submaxillary  glands,  not  by  the  sublingual  gland.  The  salivary 
secretion  of  the  strictly  carnivorous  animals  is  commonly  stated  to 
be  devoid  of  ferment;  certainly  this  holds  for  the  dog.  The  salivary 
secretion  of  the  frugivora  and  herbivora  is  rich  in  ferment,  that  of 
the  ruminantia  surprisingly  poor.     Human  saliva  is  rich  in  ferment. 

Amylase. — Under  this  term  we  include  such  ferments  as  accelerate 
the  cleavage  of  starch  and  glycogen  to  maltose,  the  hydrolysis  of 
the  polysaccharid  to  the  disaccharid.  The  older  terms  "ptyalin"  and 
"  diastase"  should  be  abandoned  in  favor  of  the  term  amylase,  which 
is  in  harmony  with  the  newer  and  generally  accepted  system  of  naming 
ferments.  The  old  conception  that  a  polysaccharid  could  by  a  single 
act  of  fermentation  be  converted  into  the  simple  hexose  has  been 
abandoned;  it  is  known  that  the  reaction  proceeds  only  to  the  stage 
of  the  disaccharid.  Thus  the  cleavage  of  starch  to  maltose  is  one  act 
of  fermentation;  the  cleavage  of  maltose  into  glucose  is  another  act 
of  fermentation.  All  the  known  starches  of  plant  or  animal  origin 
(glycogens)  are  to  be  regarded  as  polymerizations  of  maltose;  the 
hydrolysis  of  starches  yields  maltose  alone.  Whether  all  the  different 
amylases  of  plant  or  animal  origin  are  identical  is  at  present  a  question 
of  secondary  importance,  and,  furthermore,  one  of  greatest  intricacy. 
In  the  literature  of  the  technical  industries  we  read  much  of  the  "lique- 
faction ferment"  as  distinct  from  the  "  saccharification  ferment."  In 
the  case  of  malt,  for  example,  the  two  seem  quite  distinct,  and  possess 
very  different  temperature  optima.  In  human  saliva  the  distinction 
is  of  little  importance,  since  our  saliva  possesses  feeble  powers  in  the 
direction  of  the  solution  of  starch.  Human  saliva  does  digest  raw 
starch,  and  liquefaction  must  occur,  since  we  know  that  it  always 
precedes  saccharification;  but  the  velocity  of  the  reaction  is  low. 

The  amylase  is  secreted  in  an  inactive  state,  the  proferment,  in  this 
case,  therefore,  proamylase.  This  is  rapidly  changed  into  the  active 
enzyme.  According  to  our  present  conception,  this  conversion  repre- 
sents an  act  of  hydrolysis,  as  illustrated  in  the  equation : 

Proferment  +  water  =  active  ferment 
Proamylase  +  water  =  amylase. 


120  DIGESTION 

The  velocity  of  this  reaction  is  accelerated  by  acids,  alkalies,  by  salts, 
and  by  animal  extracts.  In  the  present  instance,  bacteria,  through  the 
medium  of  substances  they  elaborate,  seem  to  be  very  active. 

Qualitative  Reaction. — The  reaction  of  the  hydrolysis  of  starch  to 
maltose  is  probably  best  represented  as  follows: 

Starch. 

| 

i  ~r  i  i 

Achroodextrin  Erythrodextrin  Amylodextrin  Maltose 


I  I 

Maltose     Erythrodextrin  Achroodextrin 


Achroodextrin  Maltose 


I  I 

Achroodextrin  Maltose 

Maltose      Maltose  Maltose  Maltose 

The  hydrolysis  of  glycogen  follows  evidently  analogous  intermediary 
reactions,  as  indicated  by  the  qualitative  tests;  but  less  definite  knowl- 
edge is  here  at  hand  than  in  the  case  of  starch,  for  which  confessedly 
the  steps  given  above  have  not  been  definitely  proved. 

Conditions  of  Favorable  Action. — Amylase  acts  best  in  a  low  concen- 
tration of  acid,  not  over  a  yoifoo"-  The  fresh  saliva  is  quite  neutral, 
but  becomes  faintly  alkaline  as  the  carbon  dioxid  is  dissipated,  later 
to  become  again  acid  through  bacterial  action.  Within  these  normal 
variations  the  amylase  is  quite  regularly  active.  In  alkaline  reaction 
of  notable  degree  the  reaction  is  depressed.  An  acid  reaction  of  y^y 
inhibits  the  action.  The  presence  of  the  common  neutral  salts  in  more 
than  traces  hinders  the  action  of  the  enzyme,  higher  concentrations  tend 
to  inhibit.  No  zymo-excitor  for  this  ferment  has  ever  been  described; 
traces  of  sodium  chlorid,  of  a  neutral  phosphate,  of  peptone,  of  the 
double  tartrate  of  potassium  and  antimony,  amino-acids,  and  other 
substances  have  been  stated  to  aid  the  action  of  the  enzyme,  but  only 
in  an  incidental  manner,  and  not  after  the  fashion  of  a  true  zymo- 
excitor.  Alcohol,  even  in  small  concentrations,  seems  to  be  injurious, 
as  are  the  antiseptics  with  the  exception  of  toluol  and  chloroform. 

Quantitative  Relations  of  Reaction. — The  secretion  of  saliva  varies 
in  amount  and  in  enzymic  strength;  the  variations  occur  not  only  in 
different  individuals,  but  also  in  the  same  individual  at  different  times. 
These  facts  are  well  illustrated  in  class-room  experiments  with  saliva, 
in  which  each  student  uses  the  individual  saliva.  The  total  secretion 
varies  in  different  individuals  from  one  to  two  liters  per  day.  The 
secretion  of  water  in  the  saliva  thus  equals  or  may  exceed  that  of  the 
kidneys  and  of  the  skin  under  ordinary  circumstances.  This  water 
is,  of  course,  again  resorbed  into  the  circulation,  otherwise  the  secretion 


SALIVARY  DIGESTION  121 

would  seriously  disturb  the  equilibrium  of  the  body.  The  saliva  of 
the  periods  of  mastication  is  rich  in  ferment,  that  of  the  periods  of 
rest  poor  in  or  even  devoid  of  ferment.  To  what  extent  secretion  passes 
into  the  mouth  from  the  salivary  glands  proper  during  periods  of  rest 
has  not  been  determined.  The  act  of  mastication  of  food  is  a  direct 
and  powerful  stimulant  to  the  secretion  of  saliva  and  persons  who 
masticate  their  food  carefully  convey  into  their  stomachs  much  more 
of  the  amylase  than  do  the  individuals  who,  through  habit  or  on  account 
of  the  character  of  the  diet,  swallow  their  food  with  little  mastication. 
There  is  some  evidence  tending  to  indicate  that  the  quantity  of  saliva 
and  possibly  its  composition  may  be  dependent  upon  the  character 
of  the  diet. 

The  enzymic  activity  of  the  saliva  cannot  be  estimated  in  operation 
in  the  mouth ;  it  has  not  been  properly  measured  in  the  stomach.  There 
is,  however,  evidence  that  it  operates  more  actively  than  in  digestion 
experiments  in  vitro.  If  the  velocity  of  the  digestion  of  starch  could 
be  measured  in  the  stomach  of  an  individual  suffering  from  achlorhydria 
without  abnormal  fermentation,  the  direct  evidence  would  be  at  hand. 
The  experiment  would,  however,  suffer  from  the  presence  of  three 
uncontrollable  variables — the  resorption  of  sugar  by  the  gastric  mucosa, 
the  secretion  of  water  by  the  stomach,  and  the  passage  of  contents 
through  the  pylorus.  The  last  could  in  all  probability  be  estimated, 
but  the  resorption  of  sugar  by  the  stomach,  though  not  heavy,  could 
not  be  measured  and  the  secretion  of  water  could  not  be  controlled. 
So  far  as  I  am  aware,  no  such  experiment  has  ever  been  done,  so  we 
must  judge  alone  by  observations  of  digestion  in  glass.  If  a  1  per 
cent,  suspension  of  soluble  starch  (so-called,  meaning  starch  in  the 
gel  state)  be  digested  with  half  its  volume  of  saliva  obtained  by  the 
mastication  of  an  inert  substance  like  paraffin  or  a  gum,  maltose  will 
be  detectable  within  ten  minutes,  and  the  larger  portion  of  the  sub- 
strate will  be  split  within  four  hours.  If  the  mass  of  the  starch  be 
larger,  the  progress  of  the  reaction  will  be  delayed.  If  bacteria  be 
present,  the  activity  of  the  ferment  will  suffer  a  notable  depreciation 
after  ten  hours;  working  under  conditions  of  sterility,  as  secured  by 
the  presence  of  toluol,  the  amylase  will  retain  its  activity  for  several 
days,  though  naturally  with  progressive  loss.  Judging  from  such  diges- 
tion experiments  in  glass,  the  day's  secretion  of  saliva  would  not  be 
able  to  digest  the  day's  average  ration  of  starch,  set  at  250  grams. 
Occasionally  in  class-room  work  one  encounters  a  specimen  of  saliva 
so  rich  in  enzymic  strength  that  this  would  be  possible;  on  the  other 
hand,  however,  one  will  meet  with  other  specimens  of  saliva,  which 
in  the  quantity  of  the  day's  secretion  would  not  be  able  to  digest  over 
one-tenth  the  day's  ration  of  starch.  Certainly  the  amylase  of  the 
salivary  secretion  is  a  much  less  potent  accelerator  of  the  digestion 
of  starch  than  is  the  amylase  of  the  pancreas  or  of  the  small  intestine. 
In  the  mouth  very  little  action  can  occur,  the  time  is  too  short.  In 
the  stomach,  the  opportunity  for  action  depends  largely  upon  the  time 


122  DIGESTION 

of  appearance  and  the  concentration  of  the  hydrochloric  acid.  In 
those  individuals  in  whom  the  hydrochloric  acid  appears  in  large 
amounts  within  a  quarter  of  an  hour  after  the  ingestion  of  a  meal, 
the  digestion  of  starch  in  the  stomach  cannot  be  extensive;  in  other 
persons,  in  whom  the  secretion  of  hydrochloric  acid  is  delayed  for  an 
hour  and  is  of  low  concentration,  a  large  digestion  of  starch  may  be 
accomplished  in  the  stomach.  The  amylase  is  undoubtedly  less  sensi- 
tive to  the  action  of  hydrochloric  acid  than  has  been  currently  stated, 
and  a  notable  degree  of  digestion  of  starch  has  been  observed  in  gastric 
contents  presenting  concentrations  of  hydrochloric  acid  of  Tf^  to 
Y^-  From  one-half  to  three-fourths  of  the  starch  of  the  Ewald 
test  breakfast  will  be  dissolved  in  the  stomachs  of  many  individuals 
within  fifteen  minutes  after  the  ingestion  of  the  meal.  This  digestion, 
however,  is  largely  confined  to  the  reaction  of  liquefaction,  and  goes 
scarcely  beyond  the  stage  of  the  higher  dextrins;  little  maltose  is 
formed.  But  it  must  also  be  realized  that  some  little  time  elapses 
before  the  gastric  juice  becomes  intimately  mixed  with  the  ingesta, 
during  which  time  the  amylase  is  active.  Strongly  acid  gastric  con- 
tents, as  -^t  inhibits  the  action  of  the  amylase.  It  is  safe  to  state 
that  in  normal  individuals  not  over  one-fourth  of  the  starch  of  a  normal 
ration  is  digested  in  the  mouth  and  stomach  by  the  salivary  amylase, 
and  that  often  the  amount  will  be  as  low  as  5  per  cent.  It  is  not  likely 
that  the  ferment  normally  passes  in  an  active  state  into  the  small 
intestine.  With  lesser  degrees  of  gastric  acidity  it  is  probably,  as 
has  been  reported,  that  the  amylase  is  only  inactivated  in  the  stomach, 
not  destroyed,  and  becomes  active  again  at  alkaline  reaction.  It  can 
be  shown  in  direct  experiment  that  salivary  amylase  is  destroyed  by 
a  pronounced  peptic  digestion;  and  in  all  probability  this  process  in 
the  normal  stomach  completely  destroys  the  amylase.  Rapid  diges- 
tion of  starch  in  the  stomach  would  be  self-limited,  in  the  absence  of 
the  resorption  of  the  sugar,  since  amylase  is  practically  inactivated 
in  a  concentration  of  from  3  to  5  per  cent,  of  glucose. 

A  consideration  of  these  facts  leads  to  the  conviction  that  the  scope 
of  activity  of  the  salivary  amylase  is  comparatively  limited,  even  under 
favorable  conditions.  The  mouth,  with  its  accessory  glands,  is  essen- 
tially an  organ  of  trituration  rather  than  of  digestion;  and  the  function 
of  the  saliva  is  allied  rather  to  the  relations  of  admixtion  and  solution 
than  to  actual  digestion.  Whether  the  extirpation  of  the  salivary 
glands  would  lead  to  indirect  effects  upon  the  lower  digestive  secre- 
tions is  not  known.  One  might  be  tempted  to  invoke  the  analogy  of 
the  secretin,  but  this  ought  not  to  be  done  in  the  absence  of  direct 
experimentation. 

Variations  in  Diseases  of  the  Mouth,  Salivary  Glands,  and  Stomach. — 
The  data  upon  this  subject  are  for  the  mouth  and  salivary  glands 
quite  fragmentary;  for  the  stomach  the  facts  seem  clear.  Inflamma- 
tions of  the  mouth  that  do  not  involve  the  salivary  glands  operate  to 
disturb  salivary  digestion  by  the  establishment  of  bacterial  conditions 


SALIVARY  DIGESTION  123 

that  are  detrimental  to  the  life  and  action  of  the  ferment.  Thus  in 
case  of  stomatitis,  the  buccal  fluids  may  inactivate  the  amylase,  probably 
through  the  action  of  bacteria  or  of  products  elaborated  by  them. 
Through  the  drying  up  of  the  secretions  of  the  mouth,  the  action  of 
the  saliva  may  be  also  retarded  to  some  extent.  The  importance 
of  these  conditions  is  in  all  probability  slight;  they  are  in  practice 
far  outweighed  by  the  fact  that  in  stomatitis  mastication  is  usually 
avoided  by  the  subject. 

In  inflammations  involving  the  salivary  glands,  two  different  periods 
of  disturbance  may  be  noted.  Early,  inflammation  is  associated  with 
excessive  secretion,  the  quality  of  which  may  at  first  be  normal,  though 
later  the  ferments  are  present  in  but  sparse  amounts.  Long-continued 
inflammation  is  often  associated  with  a  deficiency  in  the  mass  of  saliva 
secreted  and  with  a  reduction  in  the  enzymic  strength.  Rarely  are 
all  the  glands  involved,  usually  only  one;  thus  the  total  function  may 
be  maintained  normally,  or  at  least  fairly  well,  by  the  uninvolved 
glands.  Prolonged  inflammation  may  lead  to  the  complete  destruction 
of  the  secreting  cells. 

Disturbances  in  the  nervous  innervation  lead  to  marked  variations 
in  the  secretion  of  the  salivary  ferments.  The  paralytic  secretion 
observed  in  some  instances  of  organic  disease  involving  the  nerves 
related  to  the  glands  is  usually  very  watery  and  feeble  in  enzymic 
power.  The  same  may  be  said  of  the  functional  forms  of  excessive 
secretion.  In  the  salivations  due  to  the  action  of  such  substances  as 
mercury  and  pilocarpin,  the  secretion  is  after  the  first  stages  deficient 
in  ferments.  As  a  rule,  it  may  be  stated  that  the  results  observed  in 
stimulation  experiments  hold  for  conditions  of  disease;  in  prolonged 
stimulation,  the  quality  of  the  secretion  is  at  first  maintained,  later 
the  fluid  is  poor  in  ferment  and  may  become  inert.  Whenever  the 
conditions  of  secretion  are  such  as  to  exhaust  the  secreting  cells  the 
result  is  an  inactive  secretion.  Vicious  habits,  like  the  vulgar  chewing 
of  tobacco  or  gum,  keep  the  salivary  glands  constantly  overworked, 
and  the  results  are  as  bad  physiologically  as  the  practices  are 
reprehensible  to  good  taste. 

In  diseases  of  the  stomach,  the  relations  are  in  the  main  clear,  subject, 
of  course,  to  the  individual  variations  that  are  to  be  observed  in  all 
the  domains  of  physiology.  Hydrochloric  acid  and  excessive  and 
abnormal  bacterial  activity  operate  to  inhibit  the  action  of  amylase 
and  destroy  it  in  the  stomach.  In  those  conditions  of  hypo-  or 
achlorhydria  not  associated  with  abnormal  and  excessive  fermentation 
of  bacterial  origin,  the  amylase  will  retain  its  normal  activity  and 
pronounced  digestion  of  starch  will  occur  in  the  stomach  under  such 
circumstances.  If,  however,  the  deficiency  of  hydrochloric  acid  be 
associated  with  abnormal  and  excessive  bacterial  fermentation,  the 
salivary  enzyme  may  be  inactivated  and  the  digestion  of  starch  will 
be  slight.  Frequently,  however,  the  conditions  do  not  operate  in  this 
manner;  despite  excessive  bacterial  action,  the  amylase  will  not  be 


124  DIGESTION 

inactivated  and  the  maltose  resulting  from  its  operation  will  be  promptly 
fermented  by  the  bacteria  after  the  cleavage  into  glucose.  This  leads 
in  practice  to  the  separation  of  two  classes  of  achlorhydria;  those  in 
which  the  presence  of  starch  in  the  diet  is  followed  by  the  formation 
of  large  amounts  of  carbon  dioxid  and  fatty  acids;  and  those  in  which 
such  fermentation  occurs  with  the  use  of  sugar  but  not  of  starch.  The 
distinction  must  be  based  upon  the  simple  fact  that  certain  cultures 
of  the  common  yeasts  and  bacteria  destroy  amylase,  while  others  do 
not;  the  value  of  the  distinction  in  dietetics  is  apparent.  There  are, 
of  course,  bacteria  that  ferment  starch,  and  in  some  instances  of  gastritis 
with  dilatation,  such  are  present  in  large  amounts  and  are  very  active, 
as  may  be  observed  in  the  expressed  gastric  contents.  As  a  rule,  how- 
ever, such  bacteria  do  not  operate  with  a  rapidity  to  be  compared 
with  the  velocity  exhibited  by  amylase;  and  the  digestion  of  starch  in 
cases  of  chronic  gastritis  with  achlorhydria  will  be  found  more  often 
to  be  due  to  saliva  than  to  the  action  of  starch-splitting  bacteria. 

The  excessive  secretion  of  hydrochloric  acid  operates  to  reduce 
the  salivary  digestion  in  the  stomach  to  the  minimum,  or  to  inhibit  it 
entirely.  This  is  obviously  but  an  exaggeration  of  the  normal  relation, 
and  is  in  all  probability  of  no  serious  detriment  to  the  subject.  So 
far  as  the  mere  absence  of  the  salivary  digestion  of  starch  and  di- 
saccharid  is  concerned,  there  is  no  evidence  that  the  complete  cessation 
of  the  function  is  of  the  slightest  injury  to  the  subject,  provided  the  act 
of  mastication  is  properly  performed;  the  motor  function  of  the  mouth 
is  paramount  to  its  chemical  function. 

As  a  rule,  in  plants  and  animals  amylase  is  accompanied  by  ferments 
for  the  cleavage  of  disaccharids.  This  is  the  case  with  the  saliva. 
The  converse  is  not  always  true  in  the  lower  plants,  many  of  which 
contain  such  ferments  without  amylase.  The  technical  separation  of 
the  two  ferments  is  possible,  and  one  can  now  procure  upon  the  market 
preparations  of  amylase  that  are  free  of  any  ferment  for  disaccharid, 
and  yield  only  maltose  as  the  result  of  their  action  upon  starch. 

Maltase. — Under  this  term  are  included  all  ferments  that  accelerate 
the  cleavage  of  maltose  to  glucose.  The  general  groups  of  ferments 
that  act  upon  the  cleavage  of  the  disaccharids  we  term  disaccharidases, 
three  of  which  are  of  great  importance  in  higher  physiology.  These 
ferments  are  not  general  but  specific  in  their  action;  maltase  acts 
upon  maltose  alone,  not  upon  cane  sugar  or  milk  sugar.  The  presence 
of  maltase  in  the  saliva  was  long  overlooked,  the  total  reaction  from 
starch  to  glucose  being  held  to  the  result  of  the  action  of  the  amylase. 
Even  now  we  know  little  more  than  that  there  are  two  ferments  con- 
cerned; beyond  the  simple  knowledge  that  a  maltase  is  present  we 
have  little  data.  It  is  secreted  by  the  same  salivary  glands  as  is  the 
amylase.  The  two  secretions  seem  to  run  parallel.  In  the  study  of 
salivary  digestion  one  realizes  that  the  stage  of  maltose  is  transient, 
the  disaccharid  is  split  into  the  two  molecules  of  diglucose  almost  as 
soon  as  formed.    In  general,  the  cleavage  of  a  disaccharid  is  a  simpler 


SALIVARY  DIGESTION  125 

and  more  rapid  reaction  than  is  the  cleavage  of  polysaccharid  to  the 
disaccharid;  and  in  working  with  a  digestion  that  includes  the  two 
superimposed  processes,  one  gets  the  impression  that  the  conditions 
of  action  of  the  maltase  are  very  favorable,  that  each  molecule  of 
maltose  is  split  practically  as  soon  as  it  appears  in  the  system.  There 
is  no  known  investigation  in  which  a  separation  of  the  maltase  from 
the  amylase  has  been  undertaken  with  human  or  mammalian  saliva. 
Under  these  circumstances  we  know  little  or  almost  nothing  of  the 
properties  of  the  salivary  maltase.  Of  indirect  evidence  we  have  not  a 
little.  A  large  number  of  experiments  have  been  done  to  determine 
the  nature  of  the  products  of  salivary  digestion  of  starch.  Some 
investigators  have  found  the  product  to  be  largely  maltose;  others 
maltose  and  isomaltose;  others  maltose  and  more  or  less  glucose;  others 
largely  glucose.  In  my  own  experience,  with  proper  dilution  of  the 
total  system  and  prolongation  of  the  time  of  digestion,  the  form  of 
sugar  has  been  found  to  be  largely  glucose.  This  can  be  shown  in  an 
experiment  that  can  be  done  in  every  laboratory.  Starch  in  dilute 
suspension  (§  per  cent.)  is  digested  with  such  volumes  of  saliva  as  will 
fully  digest  the  substrate  in  three  or  four  hours.  At  the  end  of  each 
hour,  samples  are  removed  and  treated  as  follows.  The  fluid  is  made 
alkaline  and  the  rotation  of  the  plane  of  polarized  light  measured. 
The  starch  and  dextrins  are  then  precipitated  with  methyl  alcohol, 
the  filtrate  faintly  acidulated  with  acetic  acid,  the  alcohol  removed  by 
evaporation  at  low  temperature,  the  volume  restored  to  the  original 
and  the  rotation  again  measured,  following  which  the  fluid  is  acidulated 
with  hydrochloric  acid,  heated  for  several  hours  on  a  water  bath, 
the  fluid  again  made  alkaline,  the  volume  restored  and  the  rotation 
again  measured.  It  is  my  experience  that  under  such  circumstances, 
the  third  rotation  will  not  be  much  less  than  that  observed  in  the  second, 
often  no  less.  From  this  we  conclude  that  the  sugar  present  is  largely 
glucose  rather  than  maltose.  Naturally  the  experiment  has  a  large 
range  of  error,  as  the  dextrins  are  not  entirely  insoluble  in  methyl 
alcohol,  and  there  are  numerous  manipulations  in  the  experiment. 
From  the  experiment,  furthermore,  we  may  also  conclude  that  the 
maltose  is  split  into  glucose  almost  as  rapidly  as  it  is  formed.  When 
we  consider  that  the  velocity  of  the  reaction  is  proportional  to  the 
concentration  of  the  substrate,  and  realize  how  low  is  the  concentra- 
tion of  the  maltose  in  the  experiment  described,  the  conclusion  follows 
that  the  ferment  must  be  one  of  great  activity.  The  reaction  of  the 
cleavage  of  maltose  is,  of  course,  a  simple  one  in  comparison  with  that 
of  the  cleavage  of  starch;  and  as  a  matter  of  experience  maltases operate, 
as  a  rule,  more  rapidly  than  do  amylases,  though  to  this  there  are 
exceptions.  Beyond  the  fact,  therefore,  that  the  saliva  contains  maltase 
as  well  as  amylase  and  that  the  maltase  is  probably  a  ferment  of  great 
activity,  we  know  little.  The  idea  that  the  saliva  contains  a  third 
ferment  that  is  able  to  convert  starch  directly  into  glucose,  is  devoid 
of  foundation. 


120  DIGESTION 

Saccharase  and  Lactase. — The  saliva  contains  no  ferments  capable 
of  accelerating  the  hydrolysis  of  cane  sugar  or  milk  sugar.  At  least, 
this  is  true  in  the  adult.  The  assimilation  limit  for  cane  sugar  has 
been  reported  reduced  in  animals  by  extirpation  of  the  salivary  glands. 
The  fact,  if  confirmed,  would  be  noteworthy;  but  it  does  not  lead  to 
the  inference  that  the  salivary  secretion  is  necessary  for  the  digestion 
(the  cleavage)  of  cane  sugar. 


DIGESTION   IN   THE   STOMACH 

The  amount  of  the  daily  gastric  secretion  varies  from  a  few  hundred 
cubic  centimeters  up  to  a  full  liter  or  more.  Like  the  salivary  glands, 
therefore,  the  stomach  is  an  active  organ  for  the  secretion  of  water. 
The  gastric  secretion  contains  mucus,  traces  of  salts  and  of  organic 
matters  of  unknown  nature,  hydrochloric  acid,  and  three  ferments — a 
lipase,  a  proteolytic  enzyme  termed  pepsin,  and  a  curdling  ferment 
called  chymosin.  The  hydrochloric  acid  is  supposed  to  be  secreted 
only  in  the  fundus  of  the  organ,  not  from  the  pyloric  extremity;  the 
ferments  are  secreted  from  all  parts  of  the  stomach,  but  most  actively 
from  the  pyloric  cavity;  the  mucus  is  secreted  from  all  parts.  The 
importance  of  the  mucus  is  difficult  to  estimate,  but  it  must  not  be 
overlooked  that  it  normally  combines  with  one-fourth  of  the  hydro- 
chloric acid  secreted. 

In  a  general  sense,  the  gastric  secretion  behaves  as  a  unit,  the  secre- 
tion containing  all  of  the  constituents.  A  more  exact  statement  would 
be  that  the  secretion  of  the  three  ferments  is  in  a  sense  secondary  to 
the  presence  of  the  acid.  This  is  not  strictly  true,  the  ferments  can 
be  secreted  in  traces  in  the  absence  of  the  hydrochloric  acid,  but  there 
is  much  evidence  that  the  acid  acts  as  a  powerful  stimulant  to  the 
secretion  of  the  ferments.  The  secretion  of  the  ferments  does  not, 
however,  follow  pari  passu;  wide  variations  are  observed.  The  lipase 
does  not  seem  to  follow  closely  the  other  ferments,  but  the  curdling 
ferment  seems  to  run  quite  parallel  to  the  pepsin.  The  relations  are 
different  with  secretion  into  the  empty  and  into  the  full  stomach; 
under  the  former  circumstances  the  secretion  behaves  more  as  a  unit. 
A  large  number  of  factors  are  known  to  influence  the  secretion  of  the 
gastric  juice,  both  in  quality  and  quantity;  the  line  between  the  physio- 
logical and  the  pathological  relations  is  difficult  to  draw.  Most  of 
the  facts  to  be  quoted  in  this  connection  have  been  learned  through 
investigations  on  dogs. 

The  mere  act  of  mastication  has  some  influence  upon  the  gastric 
secretion,  but  it  probably  would  not  be  marked  if  the  senses  of  taste, 
touch,  and  smell  were  excluded  from  the  experiment.  The  several 
experiments  that  are  done  to  elucidate  the  different  factors  in  gastric 
secretion  are  best  performed  upon  dogs  who  have  two  fistulas,  one 
out  of  which  the  esophagus  empties  and  a  second  at  the  pyloric  end 


DIGESTION  IN  THE  STOMACH  127 

of  the  stomach.  By  means  of  the  first  fistula,  the  animal  can  perform 
what  may  be  called  mock  or  fictitious  feeding;  the  food  is  masticated 
as  in  the  normal  and  swallowed  but  passes  out  of  the  esophageal  fistula 
and  not  into  the  stomach.  By  means  of  the  gastric  fistula,  the  gastric 
secretion  may  be  removed  directly;  and  by  this  means  the  animal  may 
be  fed  without  any  contact  of  the  food  with  the  mouth  and  removed  from 
the  senses  of  sight,  taste,  touch,  or  smell.  If  a  dog  be  given  such  a 
mock  feeding  there  is  no  chemical,  mechanical,  tactile,  or  thermic 
stimulation  of  the  mucous  membrane  of  the  stomach;  nevertheless, 
within  a  few  minutes,  the  stomach  will  begin  to  secrete  a  normal  juice, 
containing  all  the  constituents,  and  this  purposeless  secretion  will 
continue  for  a  couple  of  hours.  It  is  probable  that  this  cephalogenous 
secretion,  as  it  is  called,  is  dependent  upon  the  act  of  mastication  to 
a  slight  though  indeterminable  extent.  Section  of  the  vagi  prior  to 
feeding  will  inhibit  the  reflex  secretion;  section  of  the  vagi  after  the 
secretion  has  begun  will  not  check  it,  however,  though  it  may  reduce 
the  enzymic  strength  of  the  secretion.  It  is  believed  that  the  strongest 
factor  in  this  reflex  secretion  is  the  psychic  state  of  appetite,  that  the 
sensations  of  taste,  touch,  and  smell  have  less  effect.  Dogs  proverbially 
bolt  their  food;  their  chief  concern  seems  to  be  to  fill  the  stomach, 
the  sense  of  taste  is  given  little  consideration  by  them.  In  human 
beings,  on  the  contrary,  the  sense  of  taste  in  the  act  of  eating  is  highly 
developed.  A  repetition  of  the  experiments  on  persons  with  gastric 
fistula?,  such  as  not  infrequently  occur,  has  led  to  the  conclusion  that 
the  results  obtained  with  dogs  do  not  hold  with  men;  that  the  factors 
of  taste,  smell,  and  mastication  have  a  marked  influence  upon  the 
secretion  of  the  gastric  juice,  and  the  factor  of  appetite  is  not  pre- 
dominant as  in  the  dog.  Whether  an  individual  be  fond  or  not  of  a 
dish  has  a  marked  influence  upon  the  extent  of  reflex  gastric  secretion. 
In  this  state  of  being  fond  of  a  food,  the  factors  of  appetite,  taste, 
and  smell,  as  well  as  sight,  all  share.  In  any  event,  it  is  not  clear  how 
even  in  dogs  the  senses  of  taste,  touch,  sight,  and  smell  are  to  be  sepa- 
rated from  the  appetite,  and  to  what  extent  we  can  frame  a  conception 
of  appetite  independent  of  these  sensations.  That  the  appetite  in  a 
dog  is  of  influence  even  when  the  dog  is  fed,  is  shown  by  the  following 
experiment:  One  dog  is  fed  meat  through  its  gastric  fistula;  the  second 
dog,  following  mock  feeding,  is  given  the  same  amount  of  meat  through 
its  gastric  fistula.  In  the  second  dog  the  gastric  secretion  is  more 
abundant.  That  the  appetite  is  of  enormous  influence  upon  nutrition 
has,  of  course,  been  always  known;  to  attach  a  teleological  inference 
to  the  fact  is,  however,  unjustified. 

Mechanical  stimulation  of  the  stomach  provokes  feeble  secretion. 
Electrical  stimulation  is  effective  to  some  extent.  Thermic  stimula- 
tion is  of  some  effect;  both  heat  and  cold  increase  the  stimulating  action 
of  a  food.  Most  marked  of  all  is  the  effect  of  chemical  stimulation, 
under  which  we  understand  the  stimulation  of  foods — the  endogenous 
secretion.    To  what  extent  the  data  collected  for  the  dog  is  applicable 


128  DIGESTION 

to  man  is  not  known.  There  is,  however,  confirmatory  evidence  at 
hand. 

Viewed  from  the  standpoint  of  the  nervous  mechanism,  we  have 
two  forms  of  gastric  secretion — cerebrospinal  and  sympathetic.  Under 
cerebrospinal  secretion,  the  impulse  to  which  is  transmitted  via  the 
vagi,  are  apparently  to  be  classed  all  the  psychic,  reflex,  and  natural 
secretions  of  gastric  juice.  The  idea  of  a  secretion  dependent  upon 
the  sympathetic  system  rests  upon  the  experimental  fact  that  after 
section  of  the  vagi  and  all  other  direct  central  nervous  connections, 
if  a  portion  of  the  stomach  be  isolated  from  the  rest  of  the  organ  and 
this  restored  to  its  continuity  with  the  esophagus  and  duodenum, 
a  feeding  into  the  restored  stomach  will  be  followed  by  a  secretion 
into  the  artificial  second  stomach,  though  the  latter  is  devoid  of  all 
nervous  connections  except  by  the  sympathetic  nerves  in  the  walls 
of  the  bloodvessels.  This  experiment  today,  in  the  light  of  our  knowl- 
edge of  the  secretion  of  the  pancreatic  juice  under  the  influence  of 
secretin,  cannot,  however,  be  held  to  prove  the  occurrence  of  a 
secretion  of  sympathetic  type. 

The  normal  secretion  is  a  combination  of  the  cephalogenous  and 
endogenous  secretions.  If  a  set  of  curves  of  cephalogenous  and  endog- 
enous secretions  be  secured,  the  first  by  mock  feeding,  the  second  by 
concealed  feeding  through  the  gastric  fistula,  it  will  be  found  that  these 
when  superimposed  give  a  curve  very  much  like  that  obtained  after 
normal  feeding.  In  man  mock  feeding  gives  secretion  and  acidity  that 
are  approximately  constant  for  different  foods — meats,  bread,  milk, 
and  sugar. 

The  amount  of  the  total  secretion  is  in  a  general  way  proportional 
to  the  mass  of  the  food  ingested.  The  less  adapted  the  food  is  to  gastric 
digestion  and  the  longer  it  remains  in  the  stomach,  the  larger  the 
secretion.  Withdrawal  of  water  of  ingestion  leads  to  a  pronounced 
reduction  in  the  secretion.  The  acidity  of  the  secretion  of  the  acid- 
secreting  cells  is  believed  to  be  constant  for  each  individual;  the  varia- 
tions in  the  acidity  of  the  gastric  secretion  being,  therefore,  dependent 
upon  variations  in  the  secretion  of  water.  Extract  of  meat  is  very 
stimulating,  milk  is  but  little  less  so;  even  water  is  quite  active.  The 
most  active  juice  in  the  digestive  sense  is  obtained  following  the  inges- 
tion of  bread,  less  with  meat,  least  with  milk.  These  variations  are 
due  to  variations  in  the  secretion  of  the  ferment;  the  secretion  following 
the  ingestion  of  meat  is  the  most  acid,  there  is  less  acid  after  the  use 
of  milk,  while  after  the  ingestion  of  bread,  where  the  most  active  juice 
is  secured,  the  acidity  is  lowest.     Fats  depress  the  gastric  secretion. 

The  time  relations  also  vary.  Following  the  ingestion  of  meat,  the 
maximum  is  not  noted  for  several  hours.  Widely  current  is  the  attempt 
to  place  a  teleological  interpretation  upon  these  relations.  Thus  it 
has  been  assumed  that  a  low  acidity  is  present  in  the  digestion  of 
bread  in  order  that  the  salivary  digestion  of  the  starch  should  proceed 
as  long  and  far  as  possible.    To  read  some  of  the  published  descrip- 


DIGESTION  IN  THE  STOMACH  129 

tions,  one  might  imagine  that  the  conscious  reasoning  stomach,  on 
observing  the  nature  of  the  meal  placed  within  it,  sends  to  the  central 
nervous  system  an  order  for  so  and  so  much  hydrochloric  acid,  for 
which  excess  of  vitalism  the  investigations  are  not  to  be  held  respon- 
sible. When  the  facts  are  known  in  detail,  it  will  be  surely  found  that 
they  are  to  be  naturally  and  logically  explained  upon  the  basis  of 
physical  and  chemical  relations.  There  are  many  facts  that  suggest 
that  the  variations  in  the  secretion  of  hydrochloric  acid  in  the  stomach 
are  related  to  the  law  of  mass  action,  but  the  available  data  do  not 
now  permit  of  the  calculation  necessary  to  test  the  hypothesis.  What 
is  needed  are  quantitative  data  of  a  type  that  the  experiments  to  date 
were  not  designed  to  furnish. 

The  action  of  the  gastric  juice  upon  the  contents  of  the  stomach 
depends  in  part  upon  the  physical  state  in  which  they  were  ingested. 
As  a  rule,  it  may  be  said  that  the  stomach  begins  to  discharge  its  con- 
tents into  the  duodenum  at  the  end  of  an  hour;  and  this  process  of 
discharge  continues  from  four  to  six  hours,  sometimes  even  longer 
in  normal  individuals.  Those  portions  of  the  ingesta  that  remain 
longest  will,  of  course,  suffer  the  greatest  degree  of  digestion;  those 
that  pass  early  into  the  intestine  will  have  undergone  little  digestion. 
If  the  food  has  been  well  masticated  and  is  of  such  a  nature  as  to  remain 
in  a  condition  of  fine  subdivision  and  there  is  an  abundance  of  water 
present,  the  movements  of  the  stomach  will  be  able  within  a  short 
time  to  mix  the  ingesta  thoroughly  with  its  own  secretions  and  to 
form  an  evenly  suspended  chyme,  thus  bringing  about  conditions 
favorable  for  the  digestive  action  of  the  ferments.  Under  these  circum- 
stances, the  discharge  of  the  contents  into  the  duodenum  is  apt  to 
begin  sooner  than  otherwise.  If  the  food  be  not  well  masticated, 
proper  admixtion  does  not  occur,  the  gastric  ferments  will  have  less 
opportunity  to  act  and  portions  of  the  ingesta  may  easily  pass  into 
the  duodenum  without  having  been  in  contact  with  the  gastric  juice 
at  all.  These  facts  have  a  direct  bearing  upon  the  validity  of  the  results 
of  the  chemical  examination  of  the  gastric  contents.  If  the  expressed 
contents  be  not  soft  and  of  a  chylous  nature,  the  results  of  the  chemical 
examinations  will  have  little  value  and  cannot  be  considered  repre- 
sentative. Throughout  the  study  of  gastric  digestion,  many  facts  place 
emphasis  upon  gastric  motility  as  the  controlling  variable  in  this 
domain. 

Hydrochloric  Acid. — The  secretion  of  mineral  acid  is  a  widespread 
phenomenon  in  the  animal  kingdom.  Hydrochloric  acid  is  found  in 
the  stomach  in  all  the  known  mammals  and  birds,  and  in  many  of  the 
lower  invertebrates.  Sulphuric  acid  is  also  an  animal  secretion;  in 
several  varieties  of  marine  snails,  sulphuric  acid  is  secreted  by  glands 
lying  in  the  folds  of  the  skin  surrounding  the  pharynx  and  the  stomach, 
in  the  last-named  situation  accompanied  by  hydrochloric  acid.  The 
secretion  of  organic  acids  of  the  fatty  series  has  also  been  described 
as  occurring  in  the  stomach ;  but  this  is  doubtful,  since  bacterial  activity 
9 


130  DIGESTION 

cannot  be  absolutely  ruled  out.  Before  proceeding  to  the  discussion 
of  the  relations  of  the  hydrochloric  acid  in  the  digestion  of  protein 
in  the  stomach,  two  questions  must  be  considered.  First,  is  hydro- 
chloric acid  to  be  regarded  as  a  cellular  secretion?  Second,  under 
the  chemical  and  physical  conditions  that  are  known  to  hold  within  the 
body,  what  physico-chemical  theory  may  be  advanced  to  explain  the 
formation  of  the  hydrochloric  acid  ? 

Formation  of  Hydrochloric  Acid. — Until  recently,  it  has  been  sup- 
posed that  the  hydrochloric  acid  was  formed  within  cells  of  the  gastric 
mucosa;  in  fact,  the  older  histologists  regarded  certain  cells  as  the 
"at  id-secreting' '  cells.  For  this  specific  derivation  of  the  acid  from 
particular  cells,  the  demonstration  was  as  a  matter  of  fact  wanting; 
but  beyond  that,  no  real  doubt  was  raised  as  to  the  formation  of  the 
acid  within  the  cells  until  the  hypothesis  of  Koppe  appeared.  Accord- 
ing to  this  hypothesis  the  hydrochloric  acid  is  formed  not  in  the  cells 
lining  the  stomach,  but  in  the  lumen  of  the  stomach  itself,  upon  the 
surface  of  the  mucous  lining.  For  the  purpose  of  this  hypothesis  we 
regard  the  mucosa  of  the  stomach  as  a  semipermeable  membrane. 
Sodium  chlorid,  and  to  a  smaller  degree  other  chlorids,  are  present 
in  the  stomach,  derived  in  part  from  the  saliva  and  in  part  contained 
in  the  food.  The  undissociated  molecule  is  diffusible,  but  the  chlorion 
is  not  diffusible  through  the  gastric  mucosa.  The  cation  sodium  could 
not  diffuse  outward  from  the  stomach  unless  another  cation  diffused 
into  the  stomach.  Let  us  assume  that  this  reciprocity  occurs  between 
the  sodium  ions  of  the  gastric  contents  and  the  hydrogen  ions  of  the 
blood ;  sodium  ions  pass  from  the  lumen  of  the  stomach  into  the  blood 
and  hydrogen  ions  pass  from  the  circulation  into  the  lumen  of  the 
stomach,  the  result  being,  of  course,  the  formation  of  hydrochloric 
acid  in  the  cavity  of  the  stomach.  The  result  in  the  blood  would  be 
the  formation  of  sodium  bicarbonate.  These  bicarbonates  are  then 
supposed  to  be  secreted  by  the  pancreas,  to  combine  in  the  duodenum 
with  the  hydrochloric  acid  of  the  discharged  gastric  contents,  follow- 
ing which  the  resultant  sodium  chlorid  would  be  resorbed,  the  intestinal 
mucosa  being  held  to  be  permeable  for  both  the  sodium  and  the  chlorin 
ions. 

This  hypothesis  must  be  rejected.  The  formation  of  hydrochloric 
acid  is  not  dependent  upon  the  presence  of  chlorids  in  the  contents 
of  the  stomach;  one  can  secure  the  secretion  of  strongly  acid  gastric 
juice  in  the  entire  absence  of  any  chlorid  in  the  lumen  of  the  organ, 
nor  is  the  secretion  under  any  circumstances  parallel  to  the  chlorin 
content  of  the  viscus.  ( 'outran  to  the  earlier  ideas,  it  is  possible  under 
proper  arrangement  of  the  experiment  to  secure  the  secretion  of  hydro- 
chloric acid  in  the  dog  on  a  pure  carbohydrate  or  sugar  diet.  It  has 
been  shown  that  psychic  stimulation  of  the  appetite,  without  feeding 
or  with  mock  feeding,  both  in  the  case  of  the  isolated  stomach,  will 
had  to  the  secretion  of  notable  amounts  of  hydrochloric  acid.  In  the 
e  of  the  acid-secreting  snails,  the  S04  ion  is  not  derived  from  the 


DIGESTION  IN  THE  STOMACH  131 

medium  in  which  the  animal  is  immersed,  but  from  the  circulation. 
It  is  therefore  clear  that  the  hydrochloric  acid  is  formed  by  the  cells 
of  the  stomach  from  the  chlorids  of  the  blood.  Chlorid  starvation  leads 
to  reduction  in  the  gastric  secretion,  the  stomach  striving  to  maintain 
the  acid  concentration.  In  severe  and  prolonged  chlorid  starvation,  the 
gastric  secretion  may  be  practically  suppressed. 

What  physico-chemical  explanation  can  be  given  for  the  formation 
of  hydrochloric  acid  by  the  stomach  ?  None  today,  based  upon  quan- 
titative work.  In  the  blood  are  hydrogen  ions  derived  from  several 
sources.  The  blood  is  charged  with  carbon  dioxid,  from  whose  acid 
hydrogen  ions  are  present  through  electrolytic  dissociation.  The 
blood  contains  bicarbonates,  which  are  subject  to  both  electrolytic  and 
hydrolytic  dissociation.  The  water  of  the  blood  displays,  of  course, 
the  usual  minute  degree  of  dissociation.  The  reaction  of  native  blood 
is  neutral.  In  this  respect  it  resembles  a  weak  solution  of  sodium 
bicarbonate.  If  a  weak  solution  of  this  salt  be  prepared,  it  will  be 
found  to  have  a  slight  alkaline  reaction,  due  to  hydrolytic  dissocia- 
tion. If  the  solution  be  placed  in  a  closed  system  under  pressure  of 
carbon  dioxid  a  point  will  be  reached  where  the  reaction  of  the  solution 
will  be  neutral.  If  now  the  solution  be  placed  in  the  open,  carbon 
dioxid  will  pass  off  and  the  solution  will  return  to  its  original  faint 
alkalinity.  But  more,  on  further  exposure  to  the  air  a  part  of  the 
bicarbonate  will  be  dissociated,  the  carbon  dioxid  will  be  dissipated, 
and  a  stronger  alkaline  reaction  will  be  presented.  An  equilibrium 
will  be  finally  established  in  which  the  concentrations  of  sodium  carbo- 
nate, bicarbonate,  and  hydroxid  and  carbon  dioxid  will  participate. 
In  the  state  of  neutrality  in  which  the  blood  exists,  it  is  clear  that 
hydrogen  ions  are  available  to  the  degree  required  for  the  formation 
of  hydrochloric  acid,  since  those  withdrawn  would  be  promptly  replaced 
by  dissociation  processes  coupled  with  the  regular  production  of  carbon 
dioxid  in  the  tissues.  For  the  derivation  of  the  chlorin  ions  we  are 
much  more  in  quandary.  Chlorids  under  pressure  of  carbon  dioxid 
are  dissociated  to  some  extent  with  the  formation  of  hydrochloric 
acid;  this  can  occur  in  the  blood  to  scarcely  more  than  infinitesimal 
extent.  A  mixture  of  equivalent  parts  of  sodium  hydroxid  and  hydro- 
chloric acid  will  yield  sodium  chlorid  and  water,  with  the  faintest 
traces  of  hydrochloric  acid  and  sodium  hydroxid;  in  other  words,  the 
hydrolytic  dissociation  of  sodium  chlorid  is  so  slight  as  not  to  be  meas- 
urable. It  does  not  seem  possible  that  these  traces  of  hydrochloric 
acid  could  be  eliminated  by  the  epithelial  cells  of  the  gastric  mucosa. 
Unless  we  can  conceive  of  some  condition  whereby  the  station  of  equilib- 
rium in  these  equations  can  be  widely  shifted,  we  are  unable  to  explain 
the  formation  of  hydrochloric  acid  in  accordance  with  the  laws  of 
affinity  and  mass  action.  What  to  the  physical  chemist  is  mathe- 
matically difficult,  seems  to  the  vitalist  easy.  To  read  the  text-books 
of  physiology  written  under  the  spell  of  vitalism,  one  might  imagine 
that  the  acid-secreting  cells  are  endowed  with  tongs  wherein  they 


132  DIGESTION 

reach  into  the  circulating  blood,  pick  out  the  stray  and  wandering 
atoms  of  chlorin  and  hydrogen,  pull  them  into  their  protoplasm,  there 
unite  them,  and  then  cast  the  hydrochloric  acid  into  the  lumen  of  the 
stomach. 

Recently  a  very  interesting  hypothesis  has  been  suggested  for  the 
physico-chemical  formation  of  hydrochloric  acid,  namely,  cataphoresis. 
The  conditions  of  electrolytic  dissociation  disturb  so  seriously  the 
phenomenon  of  electrical  osmosis  that  it  has  not  yet  been  possible  to 
study  this  hypothesis  experimentally. 

Chemical  Relations. — The  hydrochloric  acid  of  the  gastric  contents 
presents  six  chemical  relations:  (a)  Direct  hydrolysis  of  protein,  the 
action  as  an  inorganic  catalyzer;  (6)  secretion  and  activation  of  the 
ferments;  (c)  action  as  zymo-excitor  for  the  pepsin;  (d)  inhibition  of  the 
activity  of  the  gastric  lipase;  (e)  inhibition  of  the  activity  of  the  salivary 
ferments,  and  (J)  inhibitory  action  upon  bacterial  fermentation.  The 
action  of  the  acid  upon  the  duodenal  mucosa,  that  operates  to  keep 
the  pylorus  closed,  will  be  described  under  the  section  of  gastric  motility, 
also  its  relation  to  the  formation  of  secretin;  the  properties  under 
d,  e,  and  /  are  discussed  under  their  appropriate  headings. 

The  hydrolysis  of  protein  by  hydrochloric  acid  is  the  classical  method 
for  the  complete  cleavage  of  a  protein  into  its  component  amino-acids. 
In  the  quantity  in  which  the  acid  is  present  in  the  stomach,  at  the 
temperature  there  maintained  and  during  the  limited  time  available, 
the  hydrolysis  of  protein  attained  in  the  stomach  under  the  catalytic 
action  of  hydrochloric  acid  is  demonstrably  very  small,  so  small  indeed 
that  it  may  be  omitted  from  our  consideration. 

The  action  of  the  hydrochloric  acid  in  stimulating  the  secretion  of 
pepsin  and  chymosin  by  the  glands  of  the  stomach  is  not  well  under- 
stood, and  is  not  susceptible  of  experimental  investigation  in  a  satis- 
factory manner.  The  activation  of  the  zymogens  of  the  proteolytic 
and  coagulating  ferments  is  to  all  appearances  normally  accomplished 
by  hydrochloric  acid.  This  action  is  simply  that  of  a  catalyzer,  the 
actual  reaction  lies  between  the  zymogen  and  water. 

Pepsinogen  +  water  =  pepsin. 

The  action  of  the  hydrochloric  acid  lies  in  a  pronounced  acceleration. 
It  is  known  that  the  unit  of  pepsin  formed  per  minute  from  pepsinogen 
is  roughly  proportional  to  the  mass  of  the  pepsinogen;  that  the  activa- 
tion within  certain  limits  is  accomplished  more  rapidly  at  higher  tem- 
perature; and  that  it  is  proportional,  within  certain  limits,  to  the  mass 
of  acid  in  the  system.  Inferentially  the  same  relations  are  assumed  to 
hold  for  the  chymosin.  In  the  absence  of  hydrochloric  acid,  pepsinogen 
if  secreted  would  be  activated  by  organic  acids  elaborated  by  bacteria 
or  by  acid  salts  of  the  diet. 

The  relation  of  the  hydrochloric  acid  to  the  enzymic  action  of  pepsin 
is  a  complicated  subject.  The  optimum  of  the  zymo-excitory  influence 
of  hydrochloric  acid  is  attained  when  there  is  present  in  a  digestion 


DIGESTION  IN  THE  STOMACH  133 

system  a  certain  amount  of  the  acid  in  excess  of  the  minimal  combining 
power  of  the  protein  there  present,  the  most  favorable  degree  of  this 
so-called  free  acidity  being  variable  with  different  preparations  of 
pepsin.  Since  hydrochloric  acid  shares  this  property  with  the  other 
acids,  the  natural  thought  would  be  to  relate  it  to  the  hydrogen  ion. 
Investigations  do  not  confirm  this  inference.  The  zymo-excitory  actions 
of  hydrochloric,  sulphuric,  phosphoric,  and  lactic  acids  do  not  run 
parallel  to  their  electrolytic  dissociation  and  are  not,  therefore,  func- 
tions of  the  concentrations  of  the  hydrogen  ions.  The  exceptional 
activity  of  hydrochloric  acid  might  be  further  supposed  to  be  due  to 
an  action  of  the  chlorion,  a  view  that  is  not  sustained  by  experiments 
with  trichloracetic  acid.  A  rather  widely  held  opinion  relates  the 
activity  of  the  hydrochloric  acid  to  the  substrate  rather  than  to  the 
ferment  in  the  direct  sense.  The  pepsin  is  supposed  to  act  not  upon 
the  protein,  but  upon  acid-protein.  According  to  this  view,  we  would 
have  the  general  scheme  of  reaction :  protein  +  acid  +  water  +  pepsin 
-»  protein-water-acid-pepsin  =  proteose  +  peptone  +  acid  +  pepsin 
.  .  .  etc.  This  point  of  view  suggests  another  explanation  of  the 
varying  activities  of  the  different  mineral  acids.  The  combination 
protein-acid  is  one  subject  to  a  very  high  degree  of  hydrolytic  disso- 
ciation; thus  the  combination  of  serum  albumin  and  hydrochloric 
acid  is  dissociated  to  over  80  per  cent.  The  hydrolytic  dissociation  of 
sulphuric-acid-protein  and  of  phosphoric-acid-protein  are  not  identical 
with  the  dissociation  of  hydrochloric-acid-protein;  and  it  might  be 
possible  to  connect  to  this  variable  of  hydrolytic  dissociation  the  vary- 
ing relations  of  acids  to  the  action  of  pepsin.  This  whole  point  of  view, 
however,  does  not  agree  well  with  the  experimental  fact  that  the  opti- 
mal concentration  of  the  acid  is  one  in  excess  of  the  combining  power 
of  the  protein  present  in  the  system.  Experimentally,  the  subject  is 
extremely  complicated;  practically  it  is  of  little  importance;  while 
theoretically  the  data  at  our  disposal  are  not  such  as  to  permit  us  to 
draw  even  approximate  conclusions. 

Quantitative  Relations.— The  quantitative  secretion  of  hydrochloric 
acid  is  subject  to  a  number  of  variables.  In  the  empty  isolated  stomach 
of  the  dog,  the  concentration  of  the  acid  in  the  secretion  is  quite  constant, 
though  the  volume  of  secretion  may  vary  widely;  the  variation  in 
different  dogs  is  surprisingly  small.  With  the  presence  of  food  and  of 
different  diets  in  the  stomach,  conditions  are  changed.  The  stomach 
does  not  present  in  the  contents  with  different  diets,  or  even  with 
varying  amounts  of  the  same  diet,  the  same  constant  concentration 
of  hydrochloric  acid.  Obviously  the  variables  for  the  secretion  of  water 
are  not  related  to  the  secretion  of  the  acid.  Under  the  discussion  of 
the  secretion  of  water  by  the  stomach,  several  variables  of  water  secre- 
tion are  defined;  the  secretion  of  water  with  the  hydrochloric  acid, 
with  the  ferments,  with  the  mucus,  and  alone,  to  which  must  be  added 
the  water  arbitrarily  present  in  the  food  and  water  of  the  saliva.  To 
these  variables  the  function  of  simple  secretion  of  water  seems  to  be 


134  DIGESTION 

compensatory,  the  stomach  obviously  strives  to  secure  in  general  a 
fairly  constant  water  content  in  the  chyme,  the  secretion  of  water 
being  in  an  approximate  sense  proportional  to  the  solid  mass  of  the  diet. 
The  total  secretion  of  hydrochloric  acid  is,  on  the  contrary,  not  related 
to  the  total  mass  of  the  diet,  but  in  an  approximate  sense  to  the  protein 
in  the  diet.  It  is  greatest  with  a  protein  diet,  least  with  a  diet  of  carbo- 
hydrate, though  present  even  if  the  diet  contain  no  protein  at  all,  as  in 
the  case  of  a  meal  of  syrup.  There  is,  however,  an  unquestioned  ten- 
dency for  the  establishment  of  a  fairly  constant  so-called  free  acidity, 
in  the  same  sense  as  there  is  the  attempt  at  the  establishment  of  a 
fairly  constant  water  content  in  the  chyme.  This  fact,  that  has  been 
given  a  highly  teleological  explanation,  admits  of  a  simple  physio- 
chemical  interpretation.  Let  it  be  assumed  that  at  a  certain  concentra- 
tion of  hydrochloric  acid  the  formation  of  the  same  is  normally  inhibited; 
it  will  be  apparent  that  the  formation  of  hydrochloric  acid  would  neces- 
sarily run  parallel  to  the  mass  of  protein  (with  which  the  acid  combines) 
in  the  meal. 

These  general  facts,  which  have  been  determined  for  the  dog,  hold 
for  human  beings  only  in  a  restricted  sense.  There  can  be  no  question 
that  for  healthy  men  and  women  living  upon  mixed,  general,  and  daily 
varied  diets,  the  facts  as  determined  for  the  dog  tend  to  hold.  But 
they  will  often  not  hold  for  individuals,  because  the  power  of  adapta- 
tion is  limited  in  many  individuals.  If  to  a  thin  woman  of  the  working 
classes,  who  naturally  lives  upon  bread,  tea,  a  few  vegetables,  and  little 
meat,  a  meal  of  fifty  or  sixty  grams  of  protein  be  given,  the  stomach 
will  not  be  able  to  secrete  enough  acid  to  combine  with  all  the  protein. 
If  the  diet  be  persisted  in,  the  stomach  will  in  a  variable  space  of  time 
adapt  itself  to  the  diet  and  present  much  higher  secretions  of  hydro- 
chloric acid.  On  the  other  hand,  if  to  an  athlete  in  training,  consuming 
large  amounts  of  meat  daily,  a  meal  low  in  protein  be  given,  the  secre- 
tion of  hydrochloric  acid  will  exceed  the  combining  power  of  the  protein, 
and  the  acid  will  be  far  in  excess  of  the  character  of  the  meal.  This 
is  only  a  physiological  illustration  of  the  pathological  fact  that  nervous 
hyperchlorhydria  cannot  be  cured  by  reduction  in  the  protein  of  the 
diet.  If  the  diet  low  in  protein  be  persisted  in  with  the  athlete,  the 
secretion  of  hydrochloric  acid  will  gradually  fall  to  that  normally  seen 
with  the  diet  under  consideration.  Jt  may  be  replied  that  such  varia- 
tions are  in  the  strict  sense  not  physiological,  but  pathological;  if  such 
a  point  of  view  be  tolerated,  we  have  then  no  means  of  defining  the 
physiology  of  human  digestion. 

The  total  secretion  of  hydrochloric  acid  in  the  human  stomach  is 
such  as  to  present  in  gastric  contents  concentrations  running  usually 
from  the  tenth  to  the  twentieth  normal,  though  higher  and  lower 
concentrations  are,  of  course,  seen.  When  one*  measures  the  total 
contents,  it  will  be  found  that  the  total  secretion  of  hydrochloric  acid 
for  the  day  may  vary  from  five  to  twenty  grams. 

Of  the  hvdrochloric  acid  in  the  stomach  two  states  exist — free  and 


DIGESTION  IN  THE  STOMACH  135 

combined  with  protein.  The  so-called  free  hydrochloric  acid  is  present 
normally  but  in  small  amount.  It  is,  however,  not  clear  just  what 
this  fraction  really  consists  in.  For  the  older  writers,  the  free  hydro- 
chloric acid  was  that  fraction  that  could  be  separated  with  certain 
color  tests,  such  as  Congo  red  and  phloroglucin  vanillin.  For  the 
modern  chemist,  the  free  hydrochloric  acid  ought  to  be  defined  as  the 
fraction  of  the  acid  that  is  dynamically  free,  revealing  itself  in  the 
electromotive  potential  and  measurable  by  its  work  as  a  catalytic 
agent.  Estimated  in  this  way,  the  free  acidity  is  not  high.  Unfortu- 
nately, the  conditions  of  hydrolytic  and  electrolytic  dissociation  are 
here  superimposed  so  that  the  arrangement  of  experiments  becomes 
difficult.  The  acid  protein  is  subject  to  a  very  high  degree  of  hydro- 
lytic dissociation.  The  fraction  of  the  acid  beyond  the  combining 
power  of  the  protein  is  presumably  dissociated  electrolytically.  The 
greater  the  amount  of  acid  present  beyond  the  amount  necessary  to 
combine  with  the  protein,  the  lower  the  absolute  hydrolytic  dissocia- 
tion of  the  acid-protein,  since  the  dissociation  is  opposed  by  the  excess 
of  the  one  component.  Furthermore,  there  is  evidence  that  with  large 
excess  of  acid,  the  relations  of  combinations  between  protein  and  acid 
are  altered;  the  higher  the  concentration  of  acid  in  a  given  system,  the 
greater  the  amount  that  will  be  combined  with  the  protein.  When 
gastric  contents  are  studied  with  the  gas  chain,  it  will  usually  be  found 
that  the  true  dynamic  potential  of  hydrogen  ions  is  not  greater  than 
is  to  be  found  in  a  hundredth  normal  acid;  often  results  as  low  as  a 
thousandth  normal  acid  are  encountered.  Occasionally  a  result  will 
be  observed  that  is  entirely  bizarre  and  susceptible  to  no  explanation. 
When  working  with  gastric  contents  of  moderate  strength,  the  result 
of  the  Congo-red  test  often  agrees  roughly  with  that  of  the  electro- 
potential  measurement;  working  with  contents  weak  in  acid,  however, 
the  paper  test  and  the  Giinzberg  test  as  well  give  much  too  high  results 
and  cannot  be  relied  upon.  Practically  the  point  is  of  little  impor- 
tance, since  the  examination  of  the  degree  of  acidity  of  gastric  contents 
is  of  diagnostic  importance  only,  the  chief  point  being  whether  free 
acidity  be  present  or  not;  whatever  the  physico-chemical  error  of  the 
color-test  methods,  the  results  are  comparable  with  each  other  and 
as  such  may  be  safely  relied  upon. 

Variations  in  Disease. — These  are  especially  of  diagnostic  impor- 
tance. The  variations  may  be  divided  into  two  large  groups — variations 
occurring  in  conditions  of  organic  disease  of  the  stomach;  and  varia- 
tions occurring  in  the  organically  sound  viscus. 

Systematically  we  may  distinguish  variations  in  the  quality  and  in 
the  quantity  of  the  gastric  secretion.  Variations  in  the  quality  of  the 
secretion  may  be  in  the  direction  of  excess  or  of  diminution.  It  is 
uncommon  to  find  an  increase  in  the  acid  in  a  pure  gastric  juice.  Usually 
the  variation  occurs  only  in  connection  with  digestion.  The  contrary 
variation,  decrease  in  the  acid,  is  common.  The  pepsin  usually  follows 
the  acid.    Variations  in  the  quantity  of  the  secretion  may  be  divided 


136  DIGESTION 

into  supersecretion  and  subsecretion.  Of  supersecretions  we  have 
transitory  and  continuous  forms,  periodic  and  occurring  in  exacerba- 
tions. In  some  instances  the  excessive  secretion  occurs  only  in  the 
course  of  digestion;  in  others  it  persists  during  the  periods  of  empty 
stomach.  Subsecretion  may  be  either  transitory  or  continuous.  Com- 
plete cessation  of  secretion  is  termed  achylia  gastrica,  and  is,  as  a  rule, 
absolute  for  both  acid  and  ferments,  though  ferments  will  usually  be 
secreted  if  acid  be  administered.  The  different  forms  of  supersecretion 
may  be  associated  with  qualitative  variations;  thus  hypochlorhydria 
is  frequent  in  supersecretion,  and  though  normal  acidity  in  concentra- 
tion is  possibly  the  more  common,  true  hy perch lorhydria  does  occur 
often  with  excessive  secretion.  With  subsecretion  hypochlorhydria 
is  the  rule.  We  are  acquainted  also  with  a  peculiar  state  of  asthenia 
of  the  secreting  mechanism;  when  food  is  ingested  there  is  active  secre- 
tion for  a  short  time,  then  sudden  cessation.  Systematic  classifications 
of  secretory  disturbances  of  the  stomach  are  of  little  value  because 
so  variable  and  so  dependent  upon  the  conditions  of  diet  and  methods 
of  investigation. 

The  variations  occurring  -in  conditions  of  structural  disease  of  the 
stomach  walls  are  to  be  divided  into  two  groups,  depending  upon 
whether  the  secretion  be  increased  or  decreased.  Increased  secretion 
of  hydrochloric  acid  associated  with  organic  disease  of  the  stomach 
is  not  very  common.  It  is  observed  as  the  rule  in  simple  ulcer  of  the 
stomach;  is  seen  sometimes  in  cases  of  gastric  carcinoma,  especially 
in  the  variety  that  has  originated  in  the  scar  of  an  ulcer;  is  seen  some- 
times in  early  inflammation  of  the  gastric  mucosa,  especially  of  the 
toxic  variety  and  is  sometimes  seen  in  cases  of  chronic  gastritis,  even 
with  dilatation  and  excessive  fermentation.  In  these  several  diseases 
the  hyperchlorhydria  may  be  intermittent  or  continuous;  and  may 
be  associated  with  excessive  secretion  of  water  or  not,  usually  not. 
The  degree  of  hyperchlorhydria  is  not  usually  excessive,  though  there 
are  exceptions  to  be  noted  in  all  the  classes  above  enumerated;  rarely 
is  the  acidity  over  double  the  normal. 

Much  more  common  is  hypochlorhydria  in  association  with  organic 
disease  of  the  stomach.  As  a  rule,  it  may  be  held  to  be  roughly  propor- 
tional to  the  intensity  of  the  disease,  though  it  cannot  be  taken  as 
indicative  of  the  integrity  or  restitutionability  of  the  tissue.  It  is  the 
rule  in  carcinoma  of  the  stomach,  as  it  is  also  in  advanced  atrophic 
gastritis,  in  simple  atrophy  of  the  mucosa  and  in  conditions  of  extreme 
cachexia.  In  simple  chronic  gastritis  of  any  type  hypochlorhydria  is 
often  seen.  The  defect  may  in  the  more  grave  cases  pass  to  complete 
failure  of  the  secretion,  though  this  is  rare  except  in  the  latest  stages 
of  the  diseases.  Usually  there  is  some  acid  secreted;  but  free  acidity 
is  not  attained  though  the  protein  in  the  diet  be  as  low  as  the  normal 
minimum,  one  gram  per  kilo  body  weight  per  day.  In  a  certain  sense 
the  defect  has  diagnostic  value,  though  exceptions  are  very  common. 
Proper  cleansing  of  the  viscus  and  care  in  diet  will  sometimes  be  followed 


DIGESTION  IN  THE  STOMACH  137 

by  partial  restoration  of  the  secretion.  In  a  large  percentage  of  instances 
of  achylia  gastrica  there  are  disturbances  in  intestine  digestion;  such 
are  also  to  be  observed  in  many  cases  of  hyperchlorhydria.  Constipa- 
tion or  diarrhea  may  be  present  in  either  type,  and  it  is  not  clear  upon 
what  these  concretely  depend. 

Variations  in  the  secretion  of  hydrochloric  acid  occurring  as  secretory 
anomalies  independent  of  organic  disease  of  the  gastric  tissues  are  very 
common.  A  slight  decrease  in  the  secretion  is  seen  in  many  diseases 
not  involving  the  stomach  organically,  as  in  chlorosis,  nephritis,  etc. 
There  are,  however,  gastric  neuroses  that  offer  this  as  their  chief  symp- 
toms. Thus  in  the  condition  known  as  achylia  gastrica,  a  normal 
stomach  will  for  days  or  weeks  at  a  time  secrete  neither  water,  acid, 
pepsin,  nor  chymosin.  Occasional  instances  of  this  sort,  not  always 
complete  and  usually  intermittent,  are  to  be  met  with  in  the  hysterical 
and  neurasthenic.  There  are  experiments  in  animals  indicating  that 
increased  bacterial  action  in  the  intestine,  leading  to  the  formation 
of  large  amounts  of  fatty  acids,  provoke  in  some  way  an  increased 
secretion  of  hydrochloric  acid  in  the  stomach. 

Much  more  common  is  functional  hyperchlorhydria.  Seen  often 
in  diseases  not  involving  the  stomach,  such  as  chlorosis,  it  occurs 
more  frequently  in  nervous  dyspepsia,  hysteria,  neurasthenia,  and  as 
a  disease  sui  generis.  Hyperchlorhydria  of  this  type  may  be  inter- 
mittent or  continuous;  it  may  occur  for  months  at  a  time  or  may  take 
place  in  veritable  crises  that  almost  overwhelm  the  sufferer.  It  may  be 
associated  with  hypersecretion  of  water  or  not;  indeed,  the  relations 
between  it  and  the  secretion  of  water  may  vary  at  different  times 
in  the  same  case.  The  degrees  of  acidity  that  may  be  seen  are  very 
striking.  Rarely  will  the  concentration  of  the  acid  be  higher  than 
fifth  normal;  but  when  to  this  is  added  heavy  hypersecretion,  the  amount 
of  acid  that  may  be  secreted  in  the  day  is  very  large.  Cases  are  seen 
in  which  the  hypersecretion  occurs  only  on  the  taking  of  food ;  in  other 
and  numerous  cases,  the  secretion  persists  in  the  empty  stomach. 
That  some  of  these  cases  develop  ulcer  of  the  stomach  or  duodenum 
is  certain;  that  most  of  them  bear  the  condition  without  consequent 
organic  lesion  seems  equally  certain. 

According  to  theory,  the  stomach  ought  to  empty  itself  more  quickly 
than  normal  in  subjects  with  hypochlorhydria,  and  to  retain  its  con- 
tents longer  than  normal  in  subjects  with  hyperchlorhydria.  In  clinical 
practice  such  results  are  not  regularly  observed.  Indeed,  some  of  the 
most  distressing  cases  of  hyperchlorhydria  are  those  in  which  the 
highly  acid  contents  are  discharged  precipitously  and  rapidly  into 
the  duodenum,  with  the  production  of  great  pain. 

The  Antiseptic  Action  of  Hydrochloric  Acid. — Normally  the  stomach 
is  a  poor  culture  tube  for  bacteria.  This  has  usually  been  ascribed  to 
the  hydrochloric  acid.  It  can  be  shown  in  culture  experiments  that 
the  concentrations  of  hydrochloric  acid  present  in  the  stomach  are 
repressive  to  bacterial  life.     On  the  other  hand,  it  is  probably  only 


138  DIGESTION 

to  certain  flora  that  hydrochloric  acid  is  bactericidal.  Every  experi- 
enced specialist  in  diseases  ot  the  stomach  has  seen  cases  of  chronic 
gastritis  with  hyperchlorhydria  associated  with  excessive  bacteria] 
fermentation. 

The  action  of  hydrochloric  acid  upon  the  intestinal  flora  is  largely 
indirect  but  nevertheless  potent.  In  the  first  place,  a  normal  gastric 
chyme,  poor  in  bacteria,  makes  for  few  bacteria  in  the  intestine. 
Secondly,  a  good  secretion  of  hydrochloric  acid  results  in  a  good  secre- 
tion of  pancreatic  juice,  so  that  the  chyme  is  promptly  digested.  The 
predigestion  of  the  proteins  of  the  diet  by  pepsin-HCl,  makes  intestinal 
digestion  most  rapid.  Free  secretion  of  gastric  juice  means  free  secre- 
tion of  pancreatic  and  intestinal  juice  and  this  leads  to  rapid  absorption. 
Anything  that  accelerates  the  velocity  of  the  intestinal  digestion  and 
absorption  of  protein  lessens  the  opportunity  for  bacterial  action. 

Pepsin. — The  secretion  of  the  stomach  contains  a  proteolytic  ferment 
in  an  inactive  state,  as  is  easily  shown  by  collecting  the  separated 
secretion  of  a  cul-de-sac  formed  in  the  pyloric  end  of  the  stomach. 
This  proferment,  propepsin,  is  activated  through  hydrolysis,  the  cata- 
lyzer for  the  reaction  being  hydrochloric  acid.  Experiments,  however, 
indicate  that  tissue  juices  and  bacterial  extracts  are  able  to  activate 
the  proferment.    This  reaction  we  now  consider  to  run  as  follows: 

Propepsin  +  water  =  pepsin 

the  catalyzer  being  as  stated  hydrochloric  acid.  That  other  factors 
operate  in  life  as  well  as  in  the  test  tube  is  shown  by  the  fact  that  it 
is  not  rare  in  the  clinic  to  find  small  amounts  of  active  pepsin  in  gastric 
contents  that  are  devoid  of  hydrochloric  acid. 

The  march  of  the  hydrolysis  of  protein  that  is  accelerated  by  pepsin, 
cannot  be  given  except  crudely,  as  in  the  case  of  starch;  there  are 
many  substages,  for  which  we  know  as  yet  but  few  indefinite  chemical 
or  physical  characteristics.  The  action  of  pepsin  is  a  limited  one,  its 
accelerating  influence  is  practically  restricted  to  the  upper  stages  of 
the  reaction,  to  the  stages  of  peptones.  Traces  of  amino-acids  occur 
rarely  in  peptic  digestion  tests;  the  bulk  of  the  material  is  not  hydro- 
lysed  beyond  the  stage  of  peptone.  While  it  is  true  that  successive 
additions  of  fresh  pepsin  will  intensify  the  reaction  and  lead  to  the 
formation  of  more  notable  amount  of  amino-acid,  the  fact  remains 
that  the  large  amounts  of  different  amino-acids  that  are  secured 
following  the  action  of  trypsin  or  erepsin  are  not  formed  in  digestion 
experiments  with  pepsin. 

Under  proteoses  we  understand  simply  proteins  that  have  lost  the 
power  of  coagulation  by  heat,  have  smaller  molecules  than  the  original 
proteins,  and  are  precipitated  by  ammonium  sulphate,  zinc  sulphate, 
tannic  acid,  and  alcohol.  The  peptones  have  still  smaller  molecules, 
possess  measurable  osmotic  pressure,  are  not  precipitated  by  ammonium 
sulphate,  but  are  still  precipitated  by  tannic  acid  and  alcohol.    In  the 


DIGESTION  IN  THE  STOMACH  139 

earlier  days  in  physiological  chemistry,  an  enormous  amount  of  work 
was  done  in  the  fractionation  of  the  albumoses  by  different  salts  and 
by  different  concentrations  of  the  same  salts.  It  is  now  clear  from 
modern  knowledge  of  physical  chemistry,  that  these  procedures  do 
not  lead  to  the  separation  of  different  chemical  individuals;  and  that 
the  older  designation  of  several  albumoses  was  purely  fictitious,  so 
far  as  the  methods  used  were  concerned.  Many  albumoses  there  are 
undoubtedly,  just  as  there  are  many  dextrins;  this  we  are  able  to  state 
from  our  general  knowledge  of  the  step-like  progression  of  the  reaction 
of  cleavage;  but  just  what  they  are,  remains  for  the  future  to  determine. 
Several  peptones  also  exist  but  we  know  little  of  them,  except  that 
they  contain  different  groupings  of  amino-acids.  The  peptone  is  cer- 
tainly the  physiological  end  product  of  the  action  of  pepsin.  All  the 
conjugated  proteins  are  split  in  the  stomach  and  the  protein  fraction 
hydrolysed  to  the  peptone  stage.     (Cf.  page  47.) 

The  question  of  the  quantitative  action  of  pepsin  on  protein  is  not 
identical  with  that  of  the  scope  of  its  action  within  the  stomach.  Under 
the  most  favorable  circumstances,  the  gastric  juice  is  in  contact  with 
the  food  for  not  over  five  to  six  hours,  which  time  will  be  shortened 
if  the  admixture  of  the  secretion  with  the  ingesta  be  delayed.  Within 
this  time,  in  tests  in  glass,  pepsin  will  not  be  able  to  do  more  than  con- 
vert native  protein  into  primary  proteose.  Careful  analyses  of  gastric 
contents  indicate  that  little  more  is  accomplished  in  the  stomach;  in 
this  case  the  digestion  in  vivo  does  not  exceed  the  digestion  in  vitro. 
If  the  pylorus  of  the  dog  be  tied  and  the  blood  supply  of  the  stomach 
cut  off  after  a  digestion  is  in  progress,  it  will  be  found,  after  ten  or  more 
hours,  that  traces  of  tyrosin  can  be  secured  from  the  gastric  contents, 
while  much  of  the  substrate  can  be  precipitated  with  ammonium 
sulphate.  In  the  human  stomach,  amino-acids  are  not  to  be  met  with 
at  all  during  the  course  of  a  normal  digestion,  nor  is  much  peptone 
formed.  The  reaction  is,  in  the  time  available,  confined  largely  to 
the  cleavage  of  the  protein  into  proteose,  and  this  may  not  be  fully 
accomplished.  Toward  the  close  of  the  period  of  gastric  digestion,  the 
reaction  is  naturally  more  advanced;  the  portions  first  passed  into 
the  duodenum  often  contain  still  coagulable  protein.  If  the  fat  in 
the  diet  be  low,  digestion  will  proceed  more  rapidly  than  if  the  meal 
be  rich  in  fat;  for  reasons  not  yet  clear,  fats  depress  the  processes  of 
gastric  digestion,  in  part  possibly  through  interference  with  solubility. 
If  one  were  to  attempt  to  measure  the  extent  of  gastric  digestion,  from 
the  point  of  view  of  the  total  work,  one  would  be  safe  in  the  statement 
that  from  one-tenth  to  one-fourth  of  the  work  of  the  digestion  of  pro- 
tein is  accomplished  in  the  stomach  under  normal  conditions.  For 
casein  in  particular  is  it  true  that  little  digestion  beyond  coagulation 
is  accomplished  in  the  stomach. 

Under  these  circumstances  the  question  arises:  What  is  the  actual 
scope  of  the  chemical  action  of  pepsin  in  the  total  process  of  digestion? 
Has  it  beyond  its  direct  action,  any  indirect  influence?    For  the  last 


140  DIGESTION 

question  we  have  a  positive  answer;  pepsin  is  of  marked  aid  to  the 
intestinal  digestion  of  protein.  Erepsin,  which  is  quite  inactive  upon 
proteins  in  their  original  state,  is  an  active  ferment  when  added  to  these 
proteins  after  the  action  of  pepsin.  Pepsin  aids  the  later  action  of 
trypsin.  A  controlled  experiment  may  be  done  to  illustrate  this.  To 
a  certain  amount  of  a  solution,  let  us  say  of  blood  serum,  a  known 
amount  of  trypsin  is  added  under  appropriate  conditions  of  alkaline 
reaction.  To  a  second  identical  amount  of  solution  of  serum,  pepsin 
and  hydrochloric  acid  are  added,  and  after  the  lapse  of  six  hours,  the 
solution  is  made  alkaline  to  the  same  degree  as  in  the  first  test,  and 
the  same  amount  of  trypsin  added.  Not  only  will  the  total  digestion 
in  the  second  test  exceed  that  in  the  first  test,  but  the  velocity  will 
be  greater.  The  gain  lies  partly  but  not  entirely  in  the  fact  that  the 
trypsin  has  an  increased  field  for  its  action,  since  the  number  of  mole- 
cules of  peptone  is  much  greater  than  of  the  native  protein.  How 
important  this  may  be  in  actual  life  is  not  known.  That  it  is  dis- 
pensable is  shown  by  the  fact  that  the  digestion  of  protein  in  usual 
amounts  is  normal  in  individuals  from  whom  the  stomach  has  been 
removed,  provided  the  diet  be  properly  arranged  as  to  administration 
and  consistency.  There  is  no  evidence  that  the  presence  of  pepsin 
has  any  other  action  upon  the  intestinal  secretion  or  processes  than 
through  its  preliminary  action  upon  the  protein.  It  is  clear,  therefore, 
that  the  estimation  of  the  peptic  secretion  of  the  stomach  is  merely 
an  estimation  of  the  secretory  state  of  the  stomach,  and  not  at  all  an 
estimation  of  the  power  of  digestion  of  protein,  on  the  part  of  either 
the  stomach  or  the  intestine.  When  one  considers  the  importance 
of  the  hydrochloric  acid  in  the  stomach  in  connection  with  its  action 
upon  the  pancreatic  secretion  it  seems  likely  that  the  acid  is  the  more 
important  factor  of  the  two,  and  from  the  standpoint  of  adaptability 
the  least  dispensable. 

Relations  to  Hydrochloric  Acid. — The  relations  of  the  activity  of 
pepsin  to  the  hydrochloric  acid  of  the  stomach  are  of  importance. 
The  relation  of  hydrochloric  acid  to  the  action  of  pepsin  must  be  held 
separate  from  its  relation  to  the  secretion  of  pepsin.  The  presence 
of  hydrochloric  acid  in  the  stomach  acts  as  a  pronounced  stimulant 
to  the  secretion  of  pepsin.  The  older  statements  that  the  two  ran 
parallel  and  that  in  the  absence  of  hydrochloric  acid  no  pepsin  would 
be  secreted  are  not  strictly  true;  but  the  fact  still  remains  that  the 
secretion  of  pepsin  in  a  stomach  devoid  of  hydrochloric  acid  will  always 
be  slight,  and  usually  it  is  entirely  wanting.  The  action  of  the  hydro- 
chloric acid  in  the  activation  of  the  pepsinogen  has  been  already  referred 
to.  While  the  secretion  of  pepsin  is  to  a  large  extent  dependent  upon 
the  presence  of  hydrochloric  acid  in  the  stomach,  beyond  that  point 
there  is  no  quantitative  parallelism;  high  acid  secretion  is  not  neces- 
sarily associated  with  high  peptic  secretion. 

The  relation  of  the  hydrochloric  acid  to  the  enzymic  activity  of 
pepsin  is  also  striking.    The  acid  itself,  of  course,  acts  as  a  catalyzer 


DIGESTION  IN   THE  STOMACH  141 

for  the  hydrolysis  of  the  proteins;  but  in  the  concentration  and  in  the 
time  and  at  the  temperature  employed,  little  measurable  action  will 
occur.  Pepsin  will  digest  feebly  at  a  neutral  reaction.  On  the  addition 
of  a  slight  amount  of  hydrochloric  acid,  the  curve  of  action  rises.  On 
further  additions  of  the  acid,  the  curve  continues  to  rise,  finally  reaches 
a  maximum  and  then  falls  rapidly  on  excessive  addition  of  acid.  With 
most  pepsins,  the  top  of  the  curve,  the  optimal  concentration  of 
acid,  will  be  found  to  run  from  tenth  to  twentieth  normal.  At  first 
sight  one  might  be  tempted  to  ascribe  this  zymo-excitor  action  to  the 
hydrogen  ions;  investigations,  however,  have  shown,  as  already  stated, 
that  it  is  not  a  function  of  that  variable  alone,  the  different  mineral 
acids  do  not  act  in  proportion  to  their  electrolytic  dissociation.  While 
the  acid  operates  to  excite  the  enzymic  power  of  the  pepsin,  it  also 
acts  as  a  catalyzer  for  the  hydrolysis  of  the  ferment;  the  descent  in 
the  curve  from  the  optimum  is  due  in  large  part  to  the  destruction 
of  the  ferment  by  the  higher  concentrations  of  acid.  In  other  words, 
the  curve  of  action  is  the  result  of  two  superimposed  processes;  and 
the  optimum  in  the  curve  is  the  point  where  the  zymo-excitory  action 
of  the  acid  is  not  appreciably  overlapped  by  the  destructive  action 
of  the  acid  upon  the  ferment.  According  to  recent  investigations  the 
mucous  membrane  of  the  stomach  possesses  the  property  of  antagoniz- 
ing the  action  of  pepsin,  and  to  the  hypothetical  substance  the  name 
anti-pepsin  has  been  given.  The  characteristics  of  this  substance  as 
stated  in  the  researches  devoted  to  it  are  rather  intangible  and  while 
anti-pepsin  may  serve  as  a  basis  for  speculation,  it  cannot  yet  serve  as 
a  basis  for  physiological  or  pathological  inference. 

Action  of  Pepsin  in  the  Intestinal  Tract. — The  action  of  the  pepsin 
is  for  practical  purposes  confined  to  the  stomach.  Pepsin  does  not 
digest  protein  to  any  extent  in  the  presence  of  bile,  even  at  an  acid 
reaction.  At  a  neutral  reaction,  a  precipitate  may  form  when  bile 
and  gastric  juice  are  mixed.  The  pepsin,  furthermore,  is  practically 
inactive  in  the  faintly  alkaline  reaction  of  the  upper  small  intestine. 
Lastly,  the  pepsin  is  rapidly  digested  by  the  trypsin.  The  result  of 
these  combined  influences  is  to  limit  sharply  the  action  of  the  pepsin 
to  the  cavity  of  the  stomach.  This  would  not  hold  so  true  if  the  con- 
tents of  the  stomach  were  discharged  en  bloc  into  the  intestine.  But 
the  contents  of  the  stomach  are  discharged  into  the  duodenum  in 
small  portions  and  the  concentration  of  hydrochloric  acid  there  is  thus 
never  permitted  to  reach  any  appreciable  degree;  and  as  the  projected 
portion  of  gastric  contents  is  soon  mixed  with  the  abundant  pancreatic 
and  intestinal  secretions,  the  destruction  of  the  pepsin  is  promptly 
accomplished. 

Variations  in  Disease. — The  question  of  the  variations  of  the  secre- 
tion of  pepsin  in  conditions  of  disease  has  not  received  the  same  attention 
that  has  been  accorded  the  variations  in  the  secretion  of  hydrochloric 
acid.  This  has  been  due  in  part  to  the  fact  that  the  variations  in  the 
concentration  of  pepsin  are  not  readily  determined;  and  by  the  general 


142  DIGESTION 

assumption  that  the  two  secretions,  as  a  usual  fact,  go  hand  in  hand. 
The  difficulty  in  the  quantitative  estimation  of  pepsin  has  not  been 
overcome.  The  figures  obtained  by  the  Mett  method  are  not  to  be 
relied  upon,  partly  because  of  the  errors  inherent  in  the  method  itself, 
and  partly  because  the  results  are  usually  calculated  according  to  the 
rule  of  Schiitz.  Now  this  rule  is  not  a  rule  of  ferment  action  at  all, 
but  simply  expresses  a  relationship  between  the  ferment  and  the  prod- 
ucts of  the  reaction  under  certain  conditions  of  concentration.  One 
could  found  a  method  for  the  approximate  quantitative  estimation 
of  pepsin  in  the  following  manner.  The  test  meal,  to  be  given  on  a 
carefully  emptied  and  cleaned  stomach,  should  always  be  of  the  same 
kind  and  amount,  both  in  solids  and  fluids.  The  time  allotted  to  the 
test  meal  in  the  stomach  should  always  be  the  same.  Then  one  would 
take  a  fixed  portion  of  the  expressed  contents  and  observe  its  action 
upon  a  standard  solution  of  a  protein  with  a  fixed  concentration  of 
hydrochloric  acid  at  a  fixed  temperature.  The  standard  solution  of 
protein  could  be  for  example,  a  1  per  cent,  solution  of  serum  albumin. 
The  measurement  of  the  velocity  of  the  reaction  could  lie  in  the  gravi- 
metric estimation  of  the  coagulable  protein.  Such  a  method,  which 
alone  would  fulfil  the  minimal  methodic  desiderata,  would  be  obviously 
arduous  and  complicated.  But  beyond  this,  the  validity  of  the  result 
would  be  made  questionable  by  several  uncontrollable  variables. 
The  secretion  of  water  in  the  stomach  is  not  parallel  to  that  of  pepsin. 
One  stomach  will  secrete  much,  another  little  water  with  the  same 
test  meal,  and  these  variations  might  be  most  pronounced  in  condi- 
tions of  disease.  The  fixing  of  the  volume  of  the  test  meal  does  not 
result  in  the  control  of  the  total  volume  of  the  gastric  contents,  upon 
which  rests  in  the  test  the  fundamentally  important  concentration 
of  the  ferment.  This  variable  might  possibly  be  controlled  by  an  esti- 
mation of  the  total  mass  of  the  gastric  contents  at  the  time  of  expression. 
But, one  can  never  be  sure  that  none  of  the  contents  have  passed  into 
the  duodenum,  unless  this  fact  can  be  determined  by  calculation  with 
figures  obtained  for  the  total  contents  of  the  stomach,  if  the  meal 
contain  some  ingredient  that  can  be  estimated.  Another  error  would 
lie  in  the  time  fixed  for  the  expression  of  the  contents,  at  the  end  of 
an  hour  or  an  hour  and  a  half.  The  relaxation  of  the  pylorus  is  in 
part  related  to  this  variable,  in  part  not.  At  any  fixed  time,  therefore, 
the  total  secretion  of  the  stomach  will  not  have  been  attained  in  some 
cases;  while  in  others  a  goodly  portion  of  the  contents  will  have  been 
already  discharged  into  the  duodenum.  A  third  difficulty  would  lie 
in  the  concentration  of  hydrochloric  acid  to  be  used  in  the  tests,  since 
the  optimum  concentration  of  hydrochloric  acid  varies  with  different 
specimens  of  gastric  contents.  Should  all  these  variables  be  under 
control,  the  result  would  still  be  relative  only.  And  it  is  clear  that 
the  results  would  not  be  of  theoretical  or  practical  value  proportional 
to  the  labor  of  the  procedure.  The  data  already  at  our  disposal  permit 
of  general  approximate  statements. 


DIGESTION  IN   THE  STOMACH  143 

In  conditions  of  disease  attended  with  excess  of  the  secretion  of 
hydrochloric  acid,  the  secretion  of  pepsin  is  usually  abundant,  without 
showing  such  excess  as  is  to  be  observed  in  the  case  of  the  acid.  This 
is  especially  true  when  the  hy perch lorhydria  is  of  the  intermittent 
type.  Defective  secretion  of  pepsin  does,  however,  occur  in  hyper- 
chlorhydria.  When  the  condition  is  continuous,  a  different  result 
will  often  be  noted.  The  glandular  cells  of  the  stomach  form  the 
pepsinogen  from  the  proteins  of  the  circulation.  This  is  a  process 
requiring  time  and  it  is  during  the  period  of  gastric  rest  that  this  storage 
of  the  cells  with  pepsinogen  occurs ;  on  the  ingestion  of  food,  the  cells 
discharge  this  inactive  ferment  and  are  then  quite  empty.  A  prolonged 
gastric  secretion  will  therefore  lead  to  the  formation  of  gastric  contents 
weak  in  pepsin;  just  as  in  the  case  of  the  parotid  gland,  prolonged 
stimulation  leads  after  a  time  to  the  secretion  of  a  saliva  feeble  in 
enzymic  strength.  In  cases  of  prolonged  hyperchlorhydria,  therefore, 
one  may  encounter  high  concentrations  of  hydrochloric  acid  with  low 
concentrations  of  pepsin.  This  may  be  seen  not  only  in  the  hyper- 
chlorhydria of  nervous  origin;  but  sometimes  also  in  cases  of  gastric 
ulcer,  one  may  see  intermittent  hyperchlorhydria  with  low  concentra- 
tions of  pepsin.  The  quantitative  maximum  is  always  lower  for  the 
ferment  than  for  the  hydrochloric  acid;  the  formation  of  the  acid  is 
obviously  much  more  easy  than  is  the  synthesis  of  the  proferment. 

In  conditions  attended  wTith  reduction  in  the  amount  of  hydro- 
chloric acid,  the  rule  observed  is  that  the  secretion  of  pepsin  sinks 
roughly  in  proportion.  To  this  rule  there  are  many  exceptions.  Espe- 
cially in  those  cases  wThere  the  secretion  of  the  hydrochloric  acid  is 
low  but  still  enough  to  combine  wTith  the  larger  part  of  the  protein  of 
a  test  meal,  do  we  often  find  the  secretion  of  pepsin  normal.  The 
corollary  of  this  fact  is  to  be  noted  in  conditions  of  nervous  achylia; 
the  administration  of  a  small  amount  of  hydrochloric  acid,  far  less 
than  the  amount  of  the  normal  secretion,  may  be  followed  by  the 
secretion  of  pepsin  in  normal  amount.  In  other  words,  the  secretion 
of  pepsin  is  not  solely  a  function  of  the  concentration  of  the  hydro- 
chloric acid.  When  the  secretion  of  the  acid  is  very  low  the  secretion 
of  pepsin  is  usually  low.  When  the  secretion  of  the  acid  is  abolished, 
there  is  usually  no  pepsin  secreted.  The  cases  of  abolition  of  secretion 
may  be  divided  conveniently  into  two  classes;  those  in  which  the 
secretion  of  pepsin  may  be  reestablished  by  the  administration  of 
hydrochloric  acid;  and  those  in  which  no  secretion  of  pepsin  follows  the 
administration  of  the  acid.  In  achylia  gastrica  of  nervous  origin, 
the  secretion  of  pepsin  can  usually  be  provoked  by  the  administration 
of  a  goodly  dose  of  hydrochloric  acid.  But  in  the  group  of  achylise 
of  grave  organic  disease,  in  advanced  cachexia,  in  carcinoma  of  the 
stomach  and  atrophic  gastritis,  the  administration  of  hydrochloric 
acid  may  have  no  effect — obviously  because  the  secreting  structures 
are  quite  completely  destroyed.  In  a  certain  sense,  therefore,  the 
results  of  the   administration  of  hydrochloric  acid   upon   the   peptic 


144  DIGESTION 

secretion  yield  a  diagnostic  indication  of  the  anatomical  state  of  the 
peptic  cells  of  the  gastric  mucosa.  As  will  be  explained  in  another 
section,  the  cessation  of  the  peptic  secretion  has  no  necessary  conse- 
quences of  practical  importance  upon  the  digestion  of  protein;  if  the 
motor  functions  of  the  stomach  are  preserved  and  the  food  is  not 
allowed  to  fall  a  prey  to  bacterial  action  within  the  stomach,  the  intes- 
tinal digestion  of  protein  in  carefully  fed  individuals  without  gastric 
secretions  is  entirely  normal. 

Chymosin. — Cbymosin  (rennet)  exists  in  the  stomach  of  all  carnivora 
and  herbivora.  It  is  not  present  in  the  human  infant  during  the  first 
few  days  after  birth,  but  the  secretion  soon  becomes  established.  It 
is  secreted  in  the  form  of  a  proferment,  termed  chymosinogen,  which 
on  standing  in  wTater  is  slowly  converted  into  the  active  rennet  through 
a  reaction  of  hydrolysis.  Hydrogen  ions  accelerate  this  conversion 
into  the  active  ferment,  and  all  acids  are,  therefore,  activators.  Alkalies 
do  not  activate,  but  destroy  the  proferment,  and  the  ferment  as  well. 

The  views  as  to  the  individuality  of  chymosin  are  divided,  some 
holding  that  it  is  identical  with  pepsin,  others  that  it  is  an  individual 
ferment.  In  the  opinion  of  the  author,  the  present  status  of  evidence 
is  in  favor  of  the  view  that  rennet  is  an  individual  ferment.  The  action 
of  chymosin  appears  to  lie  in  the  conversion  of  casein  into  an  isomer, 
paracasein.  The  idea  that  paracasein  is  a  product  of  the  hydrolysis  of 
casein  has  failed  of  direct  demonstration,  and  for  the  present  we  must 
regard  paracasein  as  an  isomer.  In  this  alone  lies  the  action  of  the 
ferment.  The  physical  phenomenon  of  coagulation  is  due  to  the  fact 
that  the  calcium  salt  of  paracasein  is  insoluble,  whereby  the  formation 
of  the  curd  occurs.  This  action  of  the  chymosin  takes  place  only  on 
neutral  or  acid  reaction.  Since,  however,  the  stomach  is  always  acid, 
either  from  hydrochloric  or  organic  acids,  the  conditions  of  favorable 
action  are  always  present.  The  action  of  the  ferment  upon  the  casein 
is  quite  rapid;  within  an  hour  at  the  outside,  often  within  a  quarter 
hour;  the  conversion  is  complete.  Alkalies  destroy  gastric  chymosin 
rapidly.  Trypsin  also  destroys  rennet,  and  it  is,  therefore,  very 
doubtful  if  it  has  any  action  within  the  intestinal  tract.  It  is  also 
very  sensitive  to  bile  and  to  bacterial  products. 

Rennet  is  a  very  active  ferment.  Of  the  prepared  chymosins,  one 
part  will  coagulate  a  half  million  parts  of  milk;  of  normal  gastric  con- 
tents one  part  will  coagulate  from  one  hundred  to  one  thousand  parts 
of  milk.  Viewed  casually,  the  phenomenon  of  coagulation  seems  a 
very  precipitous  one.  For  some  time  after  the  addition  of  the  rennet 
to  the  milk  there  is  no  sign  of  any  action;  then,  quite  suddenly,  coagula- 
tion will  set  in  and  proceed  rapidly  to  completion.  This  is  due  to  the 
fact  that  casein,  like  any  other  protein,  acts  as  a  solvent  for  the  calcium 
combination  with  paracasein;  it  is  only  when  the  casein  is  nearly  all 
converted  into  paracasein  that  the  physical  phenomenon  of  coagulation 
appears.  It  is  for  a  similar  reason  that  colostrum  does  not  coagulate; 
its  high  content  of  albumin  holds  the  paracasein  in  solution.     When 


DIGESTION  IN  THE  STOMACH  145 

the  great  activity  of  chymosin  is  understood,  it  will  be  apparent  that 
the  day's  secretion  is  more  than  sufficient  to  coagulate  the  body  weight 
of  milk,  even  in  the  adult.  Very  pronounced  reductions  in  the  secre- 
tion occur  before  the  physiological  limit  of  action  of  the  ferment  is 
reached. 

Variations  in  Disease. — These  in  general  run  parallel  to  those  of 
pepsin.  Rarely,  however,  one  will  see  gastric  contents  in  cases  of 
advanced  carcinoma  of  the  stomach  that  will  digest  protein  but  will 
not  longer  coagulate  milk.  As  a  rule,  gastric  secretions  that  are  so 
attenuated  as  to  scarcely  digest  protein,  are  still  able  to  coagulate 
milk  quite  normally,  as  so  little  of  the  ferment  is  needed  for  a  few 
hundred  cubic  centimeters  of  milk  such  as  would  be  contained  in  a 
meal  of  milk.  A  marked  reduction  in  the  coagulating  power  of  milk 
is  generally  regarded  as  possessing  more  diagnostic  importance  than  a 
heavy  reduction  in  the  secretion  of  pepsin,  as  indicating  a  greater 
destruction  of  gastric  mucosa.  In  children,  especially,  the  failure  of 
the  secretion  of  the  stomach  to  coagulate  milk  is  considered  ominous. 
The  failure  to  coagulate  milk  is  of  no  loss  to  the  organism,  so  far  as  is 
known,  since  the  trypsin  is  able  to  digest  casein  as  well  as  paracasein; 
and  in  any  event,  the  pancreatic  juice  contains  a  chymosin. 

Amylase,  Saccharase,  Maltase,  Lactase. — Ferments  of  carbohydrate 
digestion  are  not  secreted  by  the  mucous  membrane  of  the  stomach 
of  carnivora.  In  the  herbivora  such  ferments  are  secreted  in  the 
second  stomach,  but  the  anatomical  variations  are  so  great  that  the 
comparison  is  of  little  meaning.  The  stomach  contains,  of  course, 
the  amylase  and  maltase  of  the  saliva.  Concerning  the  activity  of 
these  ferments  in  the  stomach  mention  was  made  in  the  chapter  devoted 
to  salivary  digestion.  The  general  conclusion  was  that  under  normal 
conditions,  the  salivary  digestion  of  carbohydrates  in  the  stomach 
was  of  subordinate  extent  and  importance;  that  the  larger  function 
of  the  saliva  for  the  purposes  of  the  total  process  of  digestion  lay  in 
trituration,  admixtion,  and  solution  rather  than  in  the  saccharification 
of  starch  or  the  cleavage  of  maltose.  This  conclusion  is  directly  in 
line  with  the  opinion  that  the  motor  functions  of  the  stomach  have 
a  higher  importance  than  the  chemical  functions,  in  the  sense  that 
adaptation  to  the  loss  of  the  gastric  chemical  functions  is  much  more 
easily  attained  than  is  adaptation  to  the  loss  of  the  motor  functions  of 
the  stomach.  In  the  judgment  of  the  importance  of  a  given  function, 
its  relations  to  the  faculty  of  adaptation  constitutes  a  sound  guide. 
The  application  of  this  rule  teaches  us  that  the  chemical  functions 
of  the  saliva  in  the  mouth  and  stomach  are  of  subordinate  importance. 

Lipase. — The  existence  of  lipase  in  the  secretion  of  the  stomach  has 
been  until  recently  the  subject  of  disagreement.  The  contradictions 
now  in  the  literature  are  possibly  due  to  the  differences  in  the  gastric 
secretions  of  the  dog  and  of  man.  The  gastric  contents  of  the  dog 
does  not  seem  to  contain  lipase  unless  there  has  been  a  backward  flow 
of  duodenal  secretions  into  the  stomach.  When  to  a  dog  a  heavy  meal, 
10 


146  DIGESTION 

rich  in  fats,  has  been  given,  this  backward  flow  of  duodenal  juice  seems 
to  be  frequent,  if,  indeed,  not  of  regular  and  periodic  occurrence.  The 
presence  of  bile  affords  a  ready  test  of  the  exact  relations.  On  the 
other  hand,  the  gastric  contents  of  man  presents  a  lipolytic  activity 
under  conditions  where  the  admixture  of  duodenal  contents  seems 
excluded.  The  gastric  contents  expressed  an  hour  following  the  inges- 
tion of  the  Ewald  test  meal  on  an  empty  stomach  exhibit  ly  poly  tic 
activity,  will  not  digest  protein  at  an  alkaline  reaction  and  give  no 
chemical  or  spectral  signs  of  bile.  The  obvious  conclusion  is  that  the 
gastric  mucosa,  in  man  at  least,  secretes  a  lipase;  since  it  is  not  known 
in  what  state  this  ferment  is  secreted,  inferentially  it  is  in  the  state  of 
proferment. 

The  reaction  is  simply  the  cleavage  of  the  fat  or  ester  into  its  two 
components,  the  fatty  acid  and  the  alcohol,  an  act  of  hydrolysis.  Gastric 
contents  have  been  tested  upon  triacetin,  ethyl  acetate,  and  triolein, 
in  all  cases  with  positive  results.  As  to  the  comparative  activity  of 
gastric  lipase  upon  the  different  esters,  no  published  investigations 
exist. 

The  gastric  lipase  acts  to  but  slight  extent  in  the  stomach.  Since 
it  is  inactive  in  an  acid  reaction  and  its  secretion  in  the  stomach  does 
not  precede  that  of  the  hydrochloric  acid,  it  has  practically  no  field 
of  action  there. 

The  gastric  lipase  acts  in  a  neutral  or  slightly  alkaline  medium. 
Since  in  a  digestion  of  fat  free  fatty  acid  is  being  constantly  set  free, 
it  is  clear  that  the  alkali  would  be  soon  combined,  and  after  that  time 
the  reaction  would  be  very  faintly  acid ;  such  an  acidity  does  not  seriously 
disturb  the  action  of  the  ferment,  as  does  the  much  greater  inorganic 
acidity  of  the  gastric  contents.  The  failure  of  the  lipase  to  digest  fat 
in  the  stomach  is  not  due  entirely  to  the  acid  reaction,  but  partly  to 
the  absence  of  the  proper  state  of  emulsification.  In  the  chyme  mixed 
with  bile,  emulsification  is  much  better  attained,  and  under  such  condi- 
tions the  action  of  the  lipase  is  greatly  intensified. 

Variations  in  Disease. — Of  these,  little  is  known.  In  profound  organic 
disease  of  the  gastric  mucosa,  the  ferment  ceases  to  be  secreted.  Impor- 
tant probably  is  the  persistence  of  the  ferment  in  cases  of  obstruction 
of  the  pancreatic  duct.  In  many  of  these  cases  the  digestion  of  fat 
suffers  little,  sometimes  not  at  all;  in  all  cases,  with  the  presence  of 
bile  or  in  the  event  of  the  administration  of  the  fat  of  the  diet  in  a 
proper  state  of  emulsification,  a  goodly  digestion  of  fat  is  often  to  be 
secured.  For  this,  the  gastric  lipase,  together  with  that  of  the  intestine, 
must  be  held  responsible. 

Pancreatic  Juice  and  Bile  in  the  Stomach. — Careful  experimental 
investigations  on  dogs  have  recently  indicated  relations  between  the 
contents  of  the  stomach  and  duodenum  which,  if  confirmed  for  human 
beings,  promise  to  throw  light  on  obscure  questions  of  the  physiology 
and  pathology  of  the  digestive  tract.  In  dogs  the  passage  of  duodenal 
contents  into  the  stomach  is  not  seldom,  but  frequent,  and  follows 


DIGESTION  IN   THE  STOMACH  147 

certain  stimuli  and  conditions.  The  presence  of  an  excess  of  fat  or 
fatty  acids  results  in  a  prompt  transfer  of  duodenal  contents  into  the 
stomach.  While  there  can  be  little  question  that  in  man  a  lipase  is 
secreted  in  the  stomach,  it  may  well  be  that  in  cases  of  excessive  inges- 
tion of  fat,  cleavage  does  occur  in  the  stomach  as  the  result  of  the 
presence  there  of  pancreatic  lipase.  The  same  transfer  of  duodenal 
contents  into  the  stomach  may  be  observed  in  association  with 
hyperchlorhydria,  with  resultant  reduction  in  the  acidity.  There  are 
indications  that  this  may  occur  in  the  human  stomach.  It  has  been 
suggested  that  in  some  such  way  hyperacidity  may  be  physiologically 
corrected,  and  that  hyperchlorhydria  may  depend  upon  a  non-func- 
tionation  of  this  physiological  check.  On  the  other  hand,  it  is  possible 
that  some  cases  of  hypochlorhydria  may  be  due  to  an  excess  of  alkaline 
duodenal  contents  in  the  stomach.  There  seems  also  to  be  a  third 
form  of  such  discharge  of  duodenal  contents  into  the  stomach.  When 
the  stomach  is  empty,  the  pancreas  and  duodenum  are  engaged  in 
periodic  secretion.  The  stomach  is  empty  and  the  pylorus  often  open. 
Not  infrequently  in  the  dog,  this  duodenal  mixture  of  ferments  is 
discharged  into  the  stomach.  The  importance  of  such  a  situation  for 
the  question  of  the  etiology  of  ulcer  of  the  stomach  is  clear.  It  is  indeed 
possible  that  the  self-digestion  of  the  stomach,  which  is  currently 
assumed  to  be  one  stage  in  the  formation  of  gastric  ulcer,  may  be 
due  to  pancreatic  trypsin  rather  than  to  the  gastric  pepsin.  It  is  also 
possible  that  future  investigations  may  indicate  that  certain  forms  of 
indigestion  are  due  to  the  action  of  such  duodenal  secretions  and 
ferments  in  the  stomach. 

The  Secretion  of  Water. — A  widely  varying  amount  of  water  is  intro- 
duced into  the  stomach  with  the  food.  Depending  upon  the  habits 
of  the  individual,  different  amounts  of  water  are  introduced  in  the 
form  of  saliva,  varying  from  50  to  500  c.c.  per  meal.  In  the  stomach 
itself  there  are  four  states  of  secretion  of  water — with  the  ferments, 
with  the  mucus,  with  the  hydrochloric  acid,  and  directly;  it  can  be 
shown  that  these  four  avenues  of  water  secretion  are  independent. 
Apparently  the  amounts  of  water  that  are  secreted  with  the  acid, 
mucus,  and  ferments  are  roughly  constant  for  a  fixed  diet,  the  secretion 
of  water  with  the  mucus  probably  varying  most  of  all.  Least  constant 
is  the  simple  secretion  of  water,  which  is  a  variable  compensatory,  so 
to  speak,  to  the  other  secretions  of  water  and,  of  course,  to  the  amounts 
introduced  with  the  food.  Careful  investigations  on  the  dog  have 
indicated  that  under  normal  conditions  there  is  a  relation  between 
the  mass  of  the  diet  and  the  water,  the  water  content  of  the  chyme,  in 
other  words,  is  quite  constant.  Observations  upon  the  chyme  of  human 
digestion  confirm  this  conclusion.  If  the  amount  of  water  introduced 
plus  that  secreted  with  the  acid,  ferment,  and  mucus  are  sufficient 
to  produce  a  certain  consistency,  no  water  will  be  secreted  directly 
by  the  gastric  mucosa;  if  the  amount  be  insufficient,  more  water  will 
be  secreted.    Thus,  in  dogs  of  a  certain  weight,  it  has  been  found  that 


148  DIGESTION 

for  a  certain  fixed  large  mixed  meal,  the  total  water  secreted  would 
be  about  700  c.c,  this  to  be  followed  by  the  secretion  of  some  500  c.c. 
of  pancreatic  juice;  with  a  small  test  breakfast,  the  total  water  secreted 
by  the  stomach  would  be  from  150  to  200  c.c,  to  be  followed  by  the 
secretion  of  some  200  c.c.  of  pancreatic  juice.  The  converse  does  not 
hold;  if  an  excess  of  water  be  ingested,  none  will  be  absorbed  by  the 
stomach,  the  chyme  will  be  abnormally  fluid.  As  will  be  later  eluci- 
dated, the  motor  functions  of  the  stomach  are  the  most  important  of 
its  actions,  and  to  the  motor  functions  the  water  secretion  is  directly 
related. 

According  to  certain  pseudo-scientific  cults  now  prevalent,  the 
drinking  of  water  with  meals  is  held  to  be  injurious.  In  so  far  as 
the  drinking  of  water  with  the  meals  causes  the  individual  to  bolt  the 
food  and  to  neglect  proper  mastication  (the  drier  the  food  the  greater 
the  flow  of  saliva),  the  practice  of  using  water  with  the  meals  would  be 
harmful.  But  apart  from  this  it  cannot  be  injurious.  If  the  individual 
does  not  take  water  with  the  meals  it  must  be  taken  between  the  meals, 
absorbed  by  the  intestine  and  then  secreted  by  the  stomach  during 
the  period  of  gastric  digestion.  This  work  may  be  spared  by  the  con- 
sumption with  the  food,  between  the  acts  of  mastication,  of  a  moderate 
amount  of  water,  say  half  a  liter.  This  is  a  natural  practice,  is  rarely 
abused  when  plain  water  is  used,  and  not  only  cannot  be  harmful  but 
must  be  regarded  as  advantageous.  The  use  of  excessive  amounts 
of  water  or  of  other  beverages  is  harmful,  because  it  imposes  upon  the 
stomach  an  abnormal  labor,  and  upon  the  intestines  and  kidneys  also 
an  unnecessary  labor.  Herein  lies  the  greatest  harm  in  the  use  of  beer 
and  light  wines,  which  are  often,  indeed  usually,  consumed  in  excessive 
amounts. 

Variations  in  Disease. — Rarely  the  secretion  of  water  is  reduced  or 
abolished  as  a  functional  neurosis,  as  in  achylia  gastrica.  Reduction 
in  the  secretion  is  often  observed  in  grave  organic  disease  of  the  stomach, 
as  in  carcinoma,  atrophy  of  the  gastric  mucosa,  and  chronic  gastritis. 
It  is  not  the  rule,  however.  The  secretion  of  water  is  apparently  the 
last  function  lost  in  obliterative  disease  of  the  gastric  mucosa. 

Very  frequently  is  the  secretion  of  water  increased  in  disease.  As  a 
rule,  it  may  be  said  that  irritation  results  in  excessive  secretion  of  water. 
Such  hypersecretion  often  accompanies  the  secretion  of  excessive 
amounts  of  hydrochloric  acid;  nevertheless  many  cases  of  hyper- 
chlorhydria  without  total  hypersecretion  are  observed.  Hypersecretion 
of  water  with  normal  acidity  is  also  often  observed,  especially  in  chronic 
gastritis.  In  many  cases  the  acidity  is  very  low.  This  may  be  noted 
in  carcinoma  of  the  stomach,  in  atrophy  of  the  mucosa  and  in  extreme 
dilatation.  Some  of  the  most  pronounced  cases  of  total  hypersecretion 
occur  with  dilatation  of  the  stomach,  the  epithelium  of  special  type 
being  quite  totally  destroyed.  This  is  comprehensible  when  it  is  recalled 
that  in  the  atrophies  of  the  gastric  mucosa  the  special  epithelia  are 
replaced  by  cells  of  the  common  intestinal  type,  which  are  able  to 


DIGESTION  IN  THE  STOMACH  149 

secrete  mucus  and  water.    The  excessive  secretion  of  water  forms  one 
of  the  serious  features  in  the  pathology  of  dilatation  of  the  stomach. 

Secretion  of  Mucus. — Whether  the  protein  contained  in  the  gastric 
secretion  be  a  true  mucin  (a  glycoprotein)  or  a  nucleoprotein  is  not 
material  to  us  here.  The  normal  gastric  secretion  contains  a  large 
amount  of  mucus,  how  large  may  be  realized  when  it  is  stated  that 
one-fourth  of  the  normal  amount  of  hydrochloric  acid  is  combined  with 
it,  i.  e.,  the  mucus  secreted  per  day,  may  amount  to  some  20  grams. 
The  mucus  secretion  of  the  stomach  is  independent  of  the  secretion 
of  hydrochloric  acid  and  the  ferments.  Thus  high  temperature  and 
electrical  irritation  provoke  in  the  dog  the  production  of  a  neutral 
mucus  secretion.  Unlike  the  other  gastric  functions,  the  secretion  of 
mucus  cannot  be  provoked  by  psychic  or  reflex  factors,  but  is  always 
a  reaction  to  conditions  within  the  viscus.  The  mucus  has  an  unques- 
tioned physical  function  in  digestion,  which  it  shares,  of  course,  with 
that  contained  in  the  salivary  and  buccal  secretions.  The  colloidal 
and  viscous  properties  of  the  mucus  aid  in  the  proper  formation  of 
the  chyme,  in  the  same  manner  that  gumma  arabicum  aids  in  the 
preparation  of  a  permanent  suspension  and  emulsion.  If  two  portions 
of  bread  in  a  state  of  fine  subdivision  are  shaken  respectively  with  a 
fixed  amount  of  water  and  with  the  same  volume  of  water  plus  mucus, 
it  will  be  soon  noted  that  in  the  case  of  the  latter  a  totally  different 
chyme  is  produced.  Whether  the  mucus  has  other  functions  is  not 
known. 

Variations  in  Disease. — Rarely  is  the  secretion  of  mucus  reduced, 
except  in  achylia  gastrica  and  in  the  most  advanced  stages  of  organic 
disease,  when  the  lining  of  the  stomach  consists  largely  of  connective 
tissue.  Like  the  secretion  of  water,  the  secretion  of  mucus  persists 
late  in  degeneration,  atrophy,  and  obliteration  of  the  gastric  mucosa. 
On  the  other  hand,  the  secretion  is  often  excessive.  In  chronic  gastritis, 
with  or  without  dilatation,  in  carcinoma  of  the  stomach,  in  the  func- 
tional hypersecretions  with  or  without  hyperchlorhydria,  the  secretion 
of  mucus  is  often  very  excessive.  Not  only  is  the  amount  excessive, 
but  the  substance  presents  an  excessive  tenacity  and  colloidality,  the 
result  probably  of  the  action  of  organic  acids  or  bacteria  upon  it. 

Resorption  by  the  Stomach. — Great  advances  have  been  made  within 
recent  years  in  our  knowledge  of  the  relations  of  the  stomach  to  resorp- 
tion. Experimentations  by  means  of  the  Pawlow  methods  have  indi- 
cated that  the  inferences  drawn  from  experimentation  with  drugs 
and  upon  the  unisolated  stomach  could  not  be  controlled,  and  were 
in  the  larger  number  of  instances  in  error.  That  many  chemicals 
on  administration  are  absorbed  from  the  stomach  is,  of  course,  true. 
The  facts  in  pharmacology,  however,  have  necessarily  no  bearing  upon 
those  of  the  physiology  of  digestion.  We  are  now  in  the  possession  of 
sufficient  data  to  enable  us  to  indicate  quite  accurately  the  facts 
of  gastric  resorption  in  digestion. 


150  DIGESTION 

The  fats  are  not  digested  in  the  stomach,  and  there  are,  therefore, 
no  products  to  be  absorbed.  Experiments  directed  to  the  elucidation 
of  the  absorbability  of  the  higher  fatty  acids  and  glycerol  from  the 
stomach,  if  they  existed,  would  possess  but  secondary  interest,  of 
importance  only  to  the  physician  engaged  in  the  administration  of 
predigested  food.  The  available  data  tend  to  indicate  that  the  higher 
fatty  acids  would  not  be  absorbed  from  the  stomach  to  any  appreciable 
extent,  the  acid  reaction  would  cast  them  out  of  solution. 

The  most  recent  investigations  indicate  that  starches,  cane  sugar, 
maltose,  milk  sugar,  and  glucose  are  absorbed  by  the  stomach  to  but 
the  slightest  extent  in  the  dog.  This  work  has  not  been  confirmed  for 
man,  and  in  the  nature  of  the  methods  employed  cannot  be  confirmed 
except  through  accidental  circumstances.  That  sugar  will  be  absorbed 
from  the  dilated  and  ligated  organ  is  true;  but  that  fact  has  little 
bearing  upon  the  stomach  under  physiological  conditions.  The  general 
experience  with  test  meals,  when  properly  interpreted,  tends  to  confirm 
for  man  the  conclusions  that  are  known  to  hold  for  the  dog. 

The  proteins  are  digested  to  but  a  slight  extent  in  the  stomach  of 
man  normally.  About  three-fourths  of  the  protein  of  a  normal  meal  is 
converted  in  the  non-coagulable  state  in  the  stomach;  some  secondary 
proteoses  appear,  peptone  only  in  traces  if  at  all,  amino-acids  not  at 
all.  It  has  been  demonstrated  for  the  dog  that  none  of  the  products 
of  the  gastric  digestion  of  protein  are  absorbed  from  the  stomach. 
Our  best  evidence  in  man  tends  to  confirm  this  conclusion. 

The  more  finely  foods  are  subdivided,  the  more  rapidly  is  the  chyme 
formed,  and  as  a  consequence  the  stomach  is  quickly  emptied  and 
digestion  in  the  stomach  is  slight.  The  more  coarse  the  food,  the  longer 
will  it  remain  in  the  stomach,  subject  to  gastric  digestion. 

The  salts  of  the  diet  are  largely  absorbed  by  the  stomach. 

The  final  conclusion,  therefore,  is  that  the  stomach  is  not  to  be 
regarded  as  an  organ  of  resorption  so  far  as  the  processes  of  normal 
digestion  are  concerned.  That  it  does  not  normally  absorb  water, 
but  on  the  contrary  secretes  water,  has  been  pointed  out  in  detail. 

The  Motor  Functions  of  the  Stomach. — The  motor  functions  of  the 
stomach  are  twofold;  the  mixing  of  the  contents,  the  physical  prepara- 
tion of  the  chyme;  and  the  discharge  of  the  contents  into  the  duodenum. 
There  has  been  a  great  deal  of  controversy  as  to  the  modus  operandi 
of  the  gastric  movements.  It  suffices  for  us  that  in  the  normal  stomach 
the  contents  have  within  an  hour  after  ingestion  of  the  food  been  mixed 
into  a  thin  viscid  chyme,  in  which  the  solid  particles  are  in  uniform 
suspension.  The  relations  of  the  secretion  of  water  and  of  mucus  to 
the  preparation  of  the  chyme  have  been  already  elucidated.  The 
water  secretion  of  the  stomach  is  such  as  to  produce  chyme  of  quite 
constant  consistency;  and  the  mucus  aids  in  the  establishment  of  a 
minute  suspension  of  the  solid  particles.  At  the  end  of  an  hour  or 
a  little  longer  in  the  normal  stomach,  the  pylorus  is  relaxed  and  a 


DIGESTION  IN  THE  STOMACH  151 

small  amount  of  the  gastric  chyme,  probably  in  man  not  over  30  or 
40  c.c,  are  ejected  into  the  duodenum,  following  which  the  pylorus 
is  again  tightly  closed.  The  pyloric  muscles  are  under  duodenal, 
rather  than  gastric  control;  and  the  determining  factor  in  the  reflex 
appears  to  be  the  hydrochloric  acid.  The  relaxation  of  the  pylorus  is 
apparently  related  to  the  presence  in  the  duodenum  of  the  alkaline 
pancreatic  juice.  So  soon  as  the  hydrochloric  acid  has  rendered  acid 
the  contents  of  the  upper  duodenum,  the  pylorus  is  closed.  Following 
the  neutralization  of  the  hydrochloric  acid  by  the  alkali  of  the  pan- 
creatic, biliary,  and  intestinal  juices,  the  pylorus  is  again  relaxed, 
and  another  small  portion  of  chyme  is  discharged  into  the  duodenum. 
These  successive  reactions  are  repeated  until  the  stomach  is  emptied 
— a  process  requiring  from  three  to  eight  hours,  depending  upon  the 
amount  and  character  of  the  diet.  Our  data  indicate  that  this  repre- 
sents the  fundamental  and  most  important  function  of  the  stomach. 
As  will  be  elucidated  under  its  proper  heading,  when  the  gastric  chyme 
is  discharged  into  the  duodenum,  the  intestinal  digestion  and  resorption 
proceed  with  such  rapidity  that  there  is  practically  no  accumulation  of 
contents  in  the  intestine. 

Variations  in  Disease. — Reduction  in  the  motor  power  of  the  stomach 
occurs  sometimes  as  a  functional  neurosis,  but  rarely  leads  to  serious 
results.  Reduction  of  the  motor  function  of  the  stomach  occurs, 
apart  from  pyloric  obstruction,  in  connection  with  chronic  gastritis, 
atrophy  of  the  mucosa,  muscular  degeneration,  and  in  dilatation  of  the 
stomach,  however  produced.  Pyloric  obstruction  has  for  the  process 
of  digestion  the  same  meaning  as  abolition  of  motor  power.  The 
result  is  that  the  food  instead  of  being  discharged  into  the  intestine, 
lies  in  the  stomach,  the  prey  of  bacterial  processes.  Excessive  secre- 
tion of  water  often  occurs  in  these  conditions,  whereby  the  burden  of 
the  stomach  is  only  increased.  The  results  are  inanition  and  water 
starvation,  leading  to  profound  asthenia.  Since  hypochlorhydria  is 
often  seen  in  these  cases,  the  digestion  of  carbohydrates  by  the  salivary 
enzymes  continues;  as  the  sugar  is  not  absorbed  but  fermented  by 
bacteria,  the  result  is  only  further  loss.  The  peptic  digestion  is  usually 
depressed,  so  that  in  this  direction  also  digestion  suffers.  Instead 
of  being  an  organ  for  the  preparation  of  the  food  for  intestinal  diges- 
tion, the  viscus  under  these  circumstances  becomes  converted  into  a 
fermentation  tank. 

As  a  general  rule,  to  which  there  are  many  exceptions,  excess  of 
hydrochloric  acid  leads  to  prolonged  retention  of  the  chyme  in  the 
stomach,  and  deficiency  of  acid  leads  to  early  discharge  into  the  duo- 
denum. Excess  of  motor  function,  which  is  common,  has  a  meaning 
only  when  the  pyloric  reflex  is  not  maintained,  and  the  hyperactive 
stomach  is  enabled  to  discharge  its  contents  precipitously  and  in  too 
large  amounts  into  the  duodenum.  If  this  abnormality  be  pronounced, 
it  may  lead  to  diarrhea  and  enteritis,  more  especially  if,  as  will  some- 


152  DIGESTION 

times  be  the  case,  hyperchlorhydria  be  present.  More  often  there 
will  be  much  intestinal  pain,  but  the  work  of  digestion  will  be  normally 
accomplished  in  the  intestine.  Much  depends  upon  the  diet  in  these 
cases,  since  the  stomach  will  discharge  the  food  into  the  duodenum 
before  a  proper  chyme  has  been  prepared. 

General  Consideration  of  the  Functions  of  the  Stomach. — From  the 
detailed  descriptions,  it  is  clear  that  the  human  stomach  has  three 
functions;  the  digestion  of  protein  and  carbohydrates;  the  secretion 
of  water  and  mucus  and  the  preparation  of  the  chyme;  and  the  dis- 
charge of  the  chyme  into  the  duodenum.  When  contrasted  with  the 
demonstrable  importance  of  the  second  and  third  functions,  the  follow- 
ing points  in  regard  to  the  first  function  must  be  borne  in  mind.  There 
is  no  digestion  or  absorption  of  fat  occurring  in  the  stomach  at  all; 
probably  half  the  starch  of  a  normal  diet  is  liquefied  and  a  quarter 
saccharified,  none  is  absorbed;  three-fourths  of  the  protein  of  a  normal 
diet  is  converted  into  the  non-coagulable  state,  there  is  no  formation 
of  peptone  or  of  amino-acids  and  none  are  absorbed;  finally  all  the 
digestion  of  carbohydrate  can  be  easily  accomplished  in  the  intestine, 
and  the  gastric  digestion  of  protein  is  of  value  only  as  a  preparation 
for  the  intestinal  digestion  and  can  be  easily  dispensed  with.  The 
conclusion  is  positive  that  the  primary  and  most  important  functions 
of  the  stomach  are  motor,  and  the  chemical  functions  are  secondary. 
In  a  broad  way,  the  stomach  of  the  carnivora  is  not  so  different  from 
the  first  two  stomachs  of  the  herbivora  or  the  crop  and  gizzard  of 
birds.  The  chief  function  is  the  preparation  of  the  food  for  intestinal 
digestion  and  the  regulated  discharge  of  the  prepared  contents  into  the 
intestine.  Modern  experience  of  surgeons  supports  this  conclusion 
completely.  There  are  now  enough  cases  of  complete  extirpation  of 
the  stomach  to  convince  all  that  the  stomach  is  to  an  absolute  extent 
a  dispensable  organ;  such  individuals  remain  in  perfect  health  and 
nutrition,  performing  normally  all  the  processes  of  digestion  if  in  the 
culinary  preparation  of  their  food  and  in  its  frequent  administration 
the  motor  functions  of  the  stomach  are  supplanted.  Tests  in  subjects 
with  achylia  gastrica  have  indicated  that  the  intestine  is  alone  not 
well  able  to  digest  connective  tissues,  but  this  is  a  matter  of  small 
importance.  With  this  conclusion  experiences  with  pyloric  obstruc- 
tion and  gastric  dilatation  before  and  after  gastroenterostomy  are 
in  perfect  accord.  The  possession  of  a  stomach  enables  the  carnivora 
and  omnivora  to  ingest  in  one,  two,  or  three  feedings  per  day,  the 
quantum  of  food  necessary  for  the  entire  day,  just  as  the  fore  stomach 
and  psalterium  enable  the  herbivora  to  consume  the  enormous  quan- 
tities of  grass  necessary  for  their  nutrition;  in  each  instance  the  stomach, 
largely  through  its  motor  functions,  prepares  the  food  for  chemical 
digestion  and  resorption  by  the  intestine.  For  the  physician  it  is 
especially  important  that  the  relative  value  of  the  chemical  and  motor 
functions  of  the  stomach  be  understood. 


THE  PANCREAS  153 


DIGESTION   IN    THE   INTESTINE 

The  small  intestine  is  the  chief  organ  of  digestion  and  practically 
the  sole  organ  of  resorption  of  the  products  of  digestion.  The  small 
intestine  is  capable  alone  of  maintaining  the  entire  function  of  diges- 
tion; and  under  normal  circumstances  over  three-fourths  of  the  chemical 
work  of  digestion  is  accomplished  there.  Three  important  agencies 
in  digestion  operate  in  the  small  intestine;  the  pancreatic  juice,  the 
bile,  and  the  succus  entericus.  The  juice  of  the  pancreas  and  the 
succus  entericus  each  contain  practically  complete  sets  of  enzymes; 
in  a  sense  they  are  duplicate  plants.  The  bile  contains  no  enzymes, 
but  contains  important  activators  and  zymo-excitors.  The  juices  of 
the  pancreas  and  intestine  also  contain  activators.  The  relation  of 
these  three  agencies  to  the  stomach  and  to  each  other  present,  there- 
fore, interdependencies.  The  functionation  of  the  pancreas  and  of 
the  secretory  activity  of  the  small  intestine  are  dependent  upon  the 
secretions  and  the  motor  functions  of  the  stomach.  The  secretions  of 
the  pancreas  and  of  the  small  intestine  are  to  a  certain  extent  dependent 
upon  each  other.  On  the  other  hand,  physiological  experimentation 
and  observations  of  states  of  disease  have  taught  us  that  there  is  an 
enormous  power  of  adaptation  and  compensation  in  the  several  func- 
tions of  digestion;  and  that  if  the  membrane  of  resorption  be  preserved, 
the  chemical  work  of  digestion  can  be  accomplished  quite  independent 
of  the  relations  of  dependency  that  are  to  be  described.  An  important 
part  of  our  knowledge  of  intestinal  digestion  has  been  obtained  by 
experimentation  upon  animals,  largely  upon  the  dog.  In  this  pre- 
sentation, it  is  assumed  that  except  where  contradictory  data  exist, 
the  facts  thus  determined  hold  for  man. 

THE   PANCREAS 

From  the  standpoint  of  the  constituents  of  its  secretion,  the  pancreas 
is  the  most  complex  gland  in  the  body.  Its  secretion  contains  no  less 
than  six  different  and  separable  ferments,  important  activators  for 
the  intestine  and  a  varying  amount  of  alkali,  largely  in  the  form  of 
bicarbonates. 

The  pancreatic  secretion  of  alkali  is  reciprocal  to  the  gastric  secre- 
tion of  acid.  Leaving  aside  the  question  of  the  modus  operandi  of  the 
formation  of  hydrochloric  acid,  the  fact  remains  that  in  the  mucosa 
of  the  stomach  sodium  chlorid  is  split  into  its  component  ions,  the 
chlorion  passes  down  the  alimentary  tract  as  hydrochloric  acid,  the 
sodium  is  eliminated  in  large  part  by  the  pancreas  and  in  small  part 
by  the  intestine  as  sodium  bicarbonate.  In  the  lumen  of  the  small 
intestine,  they  recombine  to  form  sodium  chlorid,  which  is  resorbed  to 
reenter  the  circulation.  It  has  been  the  current  teaching  that  during 
the  period  of  secretion  of  hydrochloric  acid  the  alkalinity  of  the  blood 


154  DIGESTION 

is  increased.  While  this  might  be  expected,  since  the  sodium  that  is 
to  be  eliminated  by  the  pancreas  must  be  carried  there  by  the  circula- 
tion, as  a  matter  of  experimental  demonstration  it  has  not  been  possible 
to  prove  this.  The  reaction,  or  electromotive  potential,  of  the  blood 
is  at  all  times,  during  digestion  and  during  fasting,  quite  neutral. 
Evidently  the  sodium  is  carried  in  part  in  some  complex  undissociated 
combination  (ion  protein)  to  the  pancreas,  in  part  as  bicarbonate; 
and  this  together  with  the  tension  of  carbon  dioxid  in  the  blood  results 
in  the  maintenance  of  a  neutral  reaction.  The  reaction  of  the  pan- 
creatic juice  is,  of  course,  alkaline;  the  cells  of  the  pancreas  possess, 
therefore,  the  power  of  splitting  the  postulated  complex  sodium  protein 
combination  just  as  the  cells  of  the  stomach  possess  the  power  of  sepa- 
rating the  chlorions  from  the  sodium.  In  each  instance  the  process 
is  believed  to  rest  upon  a  physico-chemical  basis.  Since  many  of  the 
functions  of  the  pancreas  can  be  shown  to  be  dependent  upon  the 
acid  secretion  of  the  stomach,  it  might  be  questioned  whether  they 
could  be  the  result  of  the  action  on  the  pancreas  of  the  alkali  eliminated 
as  the  result  of  the  acid  secretion  of  the  stomach.  This  is,  however, 
not  the  case.  Hydrochloric  acid  introduced  into  the  stomach  has  the 
same  results  upon  the  secretion  of  the  pancreas  as  does  acid  secreted 
in  the  stomach,  except  that  the  pancreatic  elimination  of  alkali  is  in  the 
first  instance  much  less.  When  acid  is  introduced  into  the  stomach, 
this  is  in  the  intestine  (to  the  extent  that  it  is  there  neutralized) 
neutralized  largely  by  alkali  secreted  by  the  intestinal  mucosa  as  an 
abnormal  compensatory  process.  Normally  very  little  more  alkali  is 
secreted  into  the  intestinal  tract  than  necessary  to  neutralize  the  acid 
of  the  stomach — the  alkalinity  of  the  intestinal  contents  is  very  slight, 
not  over  Tinnnr- 

Relations  and  Variations  in  Pancreatic  Secretion. — The  relations  and 
variables  of  the  total  secretion  of  the  pancreas  are  known  in  but  a 
fragmentary  manner.  Acidity  in  the  gastric  secretion  or  in  the  food 
promotes  secretion;  alkaline  reaction  depresses  or  inhibits.  The  free 
use  of  water  tends  to  increase  the  volume  of  secretion.  In  the  her- 
bivora  the  secretion  is  quite  constant;  in  the  carnivora  and  in  man  the 
secretion  is  intermittent.  There  are  psychic  influences  that  may  operate 
in  a  positive  direction.  If  to  a  dog  with  esophageal,  gastric,  and  pan- 
creatic fistulse  a  mock  meal  be  given,  it  will  be  found  that  a  secretion 
of  the  pancreatic  duct  appears  some  time  before  that  of  the  stomach, 
and  therefore  independent  of  the  latter.  Variations  in  the  total 
volume  of  the  secretion  are  not  known  to  rest  upon  variations  in  the 
diet  except  in  so  far  as  these  influence  the  concentration  of  acid  in  the 
stomach.  Qualitative  variations,  however,  are  known  to  correspond 
to  variations  in  the  diet.  Thus  a  meat  meal  causes  a  secretion  very 
strong  in  ferment  (in  all  the  ferments),  bread  leads  to  the  formation 
of  a  weaker  secretion,  milk  to  the  feeblest  secretion.  It  is  necessary 
to  note  that  there  is  no  apparent  tendency  for  a  food  to  stimulate  the 
secretion  of  the  ferment  necessary  for  its  digestion;  on  the  contrary, 


THE  PANCREAS  155 

stimulation  of  one  means  stimulation  of  all.  With  pure  pancreatic 
juice,  the  proteolytic  activity  is  quite  constant  for  the  unit  of  secre- 
tion, independent  of  the  quality  or  the  type  of  food  within  the  stomach. 
Fats  exert  an  undoubted  positive  stimulation  of  the  secretion.  Extrac- 
tives and  condiments  introduced  into  the  stomach  are  without  effect 
except  through  the  secretion  of  hydrochloric  acid  that  they  may  occa- 
sion. Alcohol  depresses  the  enzymic  activity  of  the  secretion,  though 
the  total  volumn  is  somewhat  augmented. 

The  gastric  acid  is  apparently  the  chief  influence  on  the  pancreatic 
secretion.  Up  to  a  certain  point,  the  secretion  of  the  pancreas  produced 
through  the  action  of  hydrochloric  acid  in  the  stomach  displays  aug- 
menting volume  and  increasing  activity  with  increasing  concentration 
of  the  acid.  Beyond  this  point,  the  secretion  will  be  very  large  in 
amount  and  strong  in  alkali,  but  poor  in  ferments.  It  is  clear  that 
the  secretion  of  water,  of  alkali,  and  the  formation  of  ferments  are  not 
parallel  functions.  When  acid  is  introduced  into  the  stomach,  there 
is  a  latent  period  of  a  few  minutes,  following  which  the  pancreatic 
secretion  begins  to  flow.  The  influence  of  hydrochloric  acid  is  not 
a  function  of  the  chlorion  but  of  the  hydrogen  ions,  and  is,  therefore, 
common  to  all  acids.  The  action  upon  the  pancreas  can  be  shown 
not  to  be  due  to  the  withdrawal  of  the  chlorions  from  the  circulation 
or  to  the  presence  of  the  relative  excess  of  sodium  in  the  blood.  There 
is  obviously  some  form  of  circuitous  action  proceeding  from  the  lumen 
of  the  stomach  and  terminating  in  the  cells  of  the  pancreatic  gland. 
That  the  older  designation  of  reflex  nervous  action  affords  no  elucida- 
tion of  the  phenomenon,  is  clear.  It  has  been  possible,  however,  in 
part  at  least,  to  trace  this  influence  in  a  chemical  manner. 

If  an  extract  of  the  resting  intestinal  mucous  membrane  be  prepared 
and  injected  into  the  circulation,  no  secretion  of  the  pancreatic  gland 
is  to  be  noted.  If,  on  the  contrary,  the  extract  be  prepared  from  a 
section  of  intestinal  mucous  membrane  that  has  been  in  contact  with 
hydrochloric  acid,  injection  of  this  extract  will  be  followed  by  vigorous 
secretion  of  the  pancreas.  It  is  clear  that  as  the  result  of  the  action 
of  the  acid  upon  the  cells  of  the  mucosa,  a  substance  is  formed  that, 
like  pilocarpin,  is  a  stimulant  to  the  gland.  It  can  be  shown  by  the 
ablation  of  all  nervous  connections  of  the  pancreas  that  the  action  of 
the  extract  is  independent  of  the  central  nervous  system.  Direct 
injection  into  the  pancreatic  artery  gives  also  a  positive  result.  The 
same  result  may  be  secured  with  an  extract  of  the  mucous  membrane 
of  the  stomach.  To  this  hypothetical  substance  the  name  secretin  has 
been  given.  It  is  soluble  in  alcohol,  and  is  thermostable.  It  is,  there- 
fore, not  a  protein.  But  since  it  resists  ordinary  dialyzation,  it  cannot 
be  crystalloid.  It  was  originally  held  to  exist  in  the  mucosa  in  an 
inactive  state,  the  activation  being  the  result  of  the  action  of  the  acid. 
Secretin  is  not  peculiar  to  the  species,  but  derived  from  one  species 
is  active  for  all  animals.  It  has  been  shown  in  more  recent  work  that 
lower  peptones  and  polypeptids  have  a  similar  power  of  stimulating 


156  DIGESTION 

the  action  of  the  pancreas.  These  cannot,  however,  be  held  responsible 
for  the  early  secretion  of  the  pancreas  that  occurs  during  the  course 
of  gastric  digestion.  The  chemical  nature  of  secretin  is  thus  as  yet 
unknown.  But  it  is  clear  that  we  have  to  deal  with  a  striking  type 
of  phenomenon,  so  far  as  the  modus  operandi  is  concerned;  the  pan- 
creas is  stimulated  by  a  substance  from  the  alimentary  mucosa  that 
is  carried  to  it  in  the  circulation. 

The  formation  of  secretin  is  not  solely  limited  to  the  action  of  hydro- 
chloric acid.  There  is  evidence  that  the  action  of  the  bile  upon  the 
intestinal  mucosa  tends  to  stimulate  the  secretion  of  the  pancreas. 
This  is  not  an  experimental  fact,  but  simply  a  conclusion  drawn  from 
the  observation  that  bile  tends  to  accelerate  the  pancreatic  digestion 
of  protein  and  starches  as  well  as  of  fats,  in  whose  resorption  bile  is 
directly  concerned.  As  a  matter  of  fact,  however,  the  secretion  of  the 
pancreatic  juice  is  not  dependent  upon  the  formation  of  secretin,  unless 
this  formation  is  brought  about  in  more  ways  than  are  at  present 
known.  This  is  made  certain  by  the  fact  that  the  secretion  of  the 
gland  occurs  and  continues  in  the  animal  body  deprived  of  gastric 
juice  and  bile.  Either  secretin  is  not  necessary  for  the  secretion  of 
the  pancreas,  or  else  hydrochloric  acid  and  bile  are  not  the  sole  agents 
that  provoke  the  formation  of  secretin.  The  products  of  bacterial 
action  suggest  themselves  as  possible  agents.  Chloral  hydrate,  in  the 
total  absence  of  acid,  acts  upon  the  intestinal  mucosa  in  such  a  way 
as  to  stimulate  the  secretion  of  pancreatic  juice.  Maceration  of  the 
intestinal  mucosa  in  alkali  yields  also  an  extract  quite  active  as  secretin. 

Under  the  term  secretion  of  the  pancreas  we  understand  the  dis- 
charge of  the  secretion  from  the  ducts,  not  the  formation  of  the  secretion. 
In  the  carnivorous  animal,  the  formation  of  the  ferments  occur  during 
the  period  of  rest,  following  a  digestion.  The  protoplasm  of  the  cells 
of  the  acini  becomes  distended  with  granular  appearing  material, 
the  product  of  the  synthetic  action  of  the  protoplasm.  This  granular 
material  represents  the  raw  state  of  the  proferments.  The  act  of 
secretion  consists  in  the  liquefaction  (using  the  word  in  the  ordinary 
sense)  of  these  granules  and  their  discharge  through  the  lining  mem- 
branes of  the  cells  into  the  ducts. 

When  the  secretion  is  drawn  from  the  common  ducts  of  the  gland, 
it  is  devoid  of  digestive  power,  i.  e.,  the  ferments  are  in  the  state  of 
the  zymogen.  If  a  fistula  be  so  constructed  that  the  outflowing  secre- 
tion does  not  come  in  contact  with  the  duodenal  mucosa,  the  juice  will 
be  found  to  be  inactive.  Not  infrequently  (possibly  always)  a  slight 
activity  may  be  noted,  due  possibly  to  the  action  of  the  lining  cells 
of  the  ducts,  since  all  tissues,  practically,  on  maceration  yield  extracts 
that  activate  the  enzymes.  This  activation  of  the  ferments  is  here, 
as  elsewhere,  due  to  acceleration  of  an  autohydrolysis  by  the  presence  of 
some  catalytic  substance.  The  proferments  on  standing  in  water 
slowly  undergo  hydrolysis,  being  thus  converted  into  the  active  ferments. 

Zymogen  +  water  =  enzyme 


THE  PANCREAS  157 

Positively  catalytic  to  these  reactions  of  hydrolysis  whereby  the  pan- 
creatic proferments  are  activated,  are  hydrochloric  acid,  the  biliary 
salts,  bacterial  products,  and  enterokinase,  of  which  particular  mention 
will  be  made  later.  Since  bacterial  products  are  always  present  in  the 
intestinal  contents,  it  follows  that  activation  of  the  ferments,  though 
possibly  slow,  could  never  fail,  even  in  the  absence  of  bile,  gastric 
contents,  or  intestinal  juices.  On  the  other  hand,  it  is  clear  that  the 
introduction  into  the  pancreatic  duct  of  intestinal  contents  or  bile 
might  result  in  the  activation  of  the  ferments  within  the  ducts  of  the 
gland;  and  one  of  the  causes  of  disease  of  the  pancreas  is  quite  certainly 
such  abnormal  activation  of  the  ferments  within  the  ducts. 

The  function  of  the  adrenal  bodies  is  in  some  unclear  manner  con- 
nected with  the  secretion  of  the  pancreas,  and  epinephrin  can  be  shown 
to  act  as  a  stimulant  to  the  secretion.  Many  other  organs  have  been 
tested,  most  of  all  the  spleen,  for  such  problematical  action,  but  with 
negative  results.  The  total  volume  of  pancreatic  secretion  in  man  is 
not  known  definitely,  as  there  are  few  recorded  instances  of  measure- 
ments in  cases  of  accidental  or  surgical  fistulse.  It  may  probably  run 
as  high  as  half  a  liter  per  day.  Judging  by  animal  experimentation, 
hyperchlorhydria  and  the  free  drinking  of  water  would  result  in  large 
secretion. 

Our  knowledge  of  the  action  of  the  several  ferments  of  the  pancreatic 
secretion  is,  for  obvious  reasons,  less  extensive  than  in  the  case  of  the 
ferments  of  salivary  or  gastric  secretion.  Many  of  the  studies  of  the 
pancreatic  ferments  have  been  carried  out  with  dry  preparations  of 
the  glands,  and  such  investigations  cannot  be  expected  to  yield  final 
data. 

Amylase. — The  pancreatic  juice  contains  an  active  amylase,  a  more 
powerful  ferment  than  is  found  in  the  saliva,  in  particular  more  active 
in  the  hydrolysis  of  raw  starch.  It  is  secreted  in  the  inactive  state 
and  is  activated  by  the  bile,  the  succus  entericus,  and  possibly  also 
by  bacterial  products  and  by  acids.  It  is  not  possible,  with  the  use  of 
either  starch  or  glycogen  as  the  substrate,  to  determine  that  the  qualita- 
tive action  of  the  ferment  is  in  any  way  different  from  that  of  the 
saliva.  The  amylase  of  one  secretory  period  of  the  pancreas  is  able 
within  a  few  hours  to  convert  into  sugar  several  hundred  grams  of 
cooked  starch,  aided,  of  course,  by  the  preceding  action  of  the  salivary 
amylase  and  the  accompanying  action  of  the  intestinal  amylase;  the 
reaction  is  usually  complete,  t.  e.,  the  feces  contain  no  undigested 
starch.  Were  the  action  of  these  ferments  not  complete,  bacteria 
would  in  all  probability,  in  the  absence  of  diarrhea,  often  ferment  the 
undigested  starch.  It  is  a  common  experience  of  those  engaged  in 
the  analyses  of  stools  to  find  occasional  particles  of  undigested  starch. 
Such  are  usually  due  to  improper  cooking  or  to  imperfect  mastication. 
On  the  other  hand,  how  effective  may  be  the  digestion  of  uncooked 
starch,  when  the  foods  are  properly  masticated,  is  illustrated  by  the 
normal  digestion  to  be  noted  in  the  adherent  of  the  sects  who,  like 


158  DIGESTION 

the  herbivora,  consume  only  raw  food.  We  read  so  much  of  the  proper 
baking  of  bread  and  of  the  completed  cooking  of  cereals;  yet  there  are 
whole  colonies  of  diet  fadists,  adults  and  children,  who  masticate 
and  digest  raw  grains. 

The  conditions  for  the  favorable  action  of  the  amylase  have  not  been 
worked  out.  The  reaction  optimum  is  a  very  slight  degree  of  alkalinity, 
about  unnnr  Good  fermentation  is  to  be  noted  at  neutral  reaction, 
and  even  some  action  at  slight  acidity.  High  alkalinity  depresses 
strongly,  though  excess  of  alkalinity  is  better  borne  than  excess  of  acid. 
In  each  instance  the  depression  is  due  to  destruction  of  the  ferment, 
not  to  inhibition  of  the  activity.  So  far  as  known,  none  of  the  varia- 
tions in  the  reaction  of  the  normal  digestive  tract  could  disturb  appre- 
ciably the  activity  of  this  ferment.  The  normal  stools  do  not  usually 
contain  amylase  that  can  be  shown  to  be  separated  from  the  bodies 
of  the  fecal  bacteria.  Contrary  findings  are,  however,  often  noted, 
especially  with  diarrhea  or  purgation.  Apparently  the  bacterial  pro- 
cesses in  the  lower  intestinal  tract,  probably  in  the  colon,  destroy  the 
ferment.  In  the  presence  of  starch,  the  ferment  is  quite  resistant; 
in  the  absence  of  starch,  which  is  the  normal  condition  in  the  colon, 
the  ferment  is  sensitive.  This  fact  is  of  importance,  since  it  teaches 
that  we  cannot  count  upon  amylolytic  action  in  the  colon  in  the  use 
of  rectal  alimentation.  The  presence'  or  absence  of  amylase  in  the 
stools  cannot  be  employed  as  a  reliable  test  of  the  presence  or  absence 
of  pancreatic  secretion  in  the  intestine. 

Maltase. — Of  the  maltase  of  the  pancreatic  juice  still  less  is  known. 
The  existence  of  maltase  in  the  pancreatic  juice  has  indeed  been  denied ; 
in  all  events  it  is  subordinate  to  the  intestinal  maltase  in  importance. 
Unlike  the  amylase  it  is  not  of  high  activity.  The  utilization  of  maltose 
proceeds  apparently  quite  as  rapidly  as  that  of  glucose,  so  that  the 
digestion  of  starch,  in  which,  of  course,  the  pancreatic  ferment  plays 
only  one  part,  must  be  very  rapid.  What  little  is  known  of  the  favor- 
able conditions  of  action  correspond  to  what  has  been  stated  for  amyl- 
ase. It  is  apparently  very  easily  activated,  since  under  the  conditions 
of  procurement  in  which  the  pancreatic  juice  is  obtained  inactive  as 
to  trypsin  and  lipase,  the  maltase  is  active,  yet  it  can  be  shown  to 
be  secreted  in  the  inactive  state.  It  is  a  ferment  very  sensitive  to 
untoward  chemical  influences.  The  normal  stools  contain  no  maltase 
not  connected  with  fecal  bacteria — important  again  in  relation  to  rectal 
alimentation. 

Invertase  and  Lactase. — Invertase  is  not  present  in  the  pancreatic 
juice — all  searches  have  been  negative.  The  digestion  of  cane  sugar 
is,  therefore,  outside  the  scope  of  the  pancreatic  secretion.  This  fact 
holds  for  herbivora  as  well  as  for  carnivora,  and  corresponds  to  the 
fact  in  the  salivary  secretion. 

Whether  lactase  exists  in  the  pancreatic  juice  of  the  adult  is  doubtful. 
Nearly  all  investigations  have  led  to  negative  results.  A  few  have 
found  indications  of  the  cleavage  of  milk  sugar  with  the  use  of  the 


THE  PANCREAS  159 

pancreatic  juice  for  young  animals  after  a  period  of  milk  diet,  but 
even  here  the  experimental  results  have  not  been  clear-cut.  The  wide- 
spread occurrence  of  invertase  and  lactase  in  bacteria  renders  the 
question  difficult  of  study.  For  the  present,  it  will  be  safest  to  state 
that  the  cleavage  of  cane  sugar  and  of  milk  sugar  are  functions  of  the 
succus  enter icus  alone. 

Emulsin. — There  is  no  question  that  glucosids  are  hydrolyzed  in  the 
intestinal  tract  of  man  and  of  the  higher  animals.  This  might  be 
due  to  an  emulsin  in  the  pancreatic  juice,  in  the  succus  entericus,  or 
to  a  ferment  derived  from  bacteria,  many  of  which  have  this  function. 
It  now  seems  clear  that  the  pancreatic  juice  contains  no  emulsin — this 
is  contained  only  in  the  succus  entericus.  The  term  emulsin  is  used 
generically,  since  the  faculty  of  the  intestinal  tract  has  not  been 
systematically  tested  upon  glucosids. 

Lipase. — To  this  ferment  belongs  one  of  the  most  important  properties 
of  the  pancreatic  juice,  the  cleavage  of  fat.  The  ferment  is  secreted 
in  an  entirely  inactive  state!  It  is  activated  by  bile,  by  the  succus 
entericus,  and  by  bacterial  products.  Gastric  contents  also  have  the 
property  of  activation,  though  the  hydrochloric  acid  is  destructive 
to  the  ferment.  The  ferment  is  a  very  active  one.  Its  action  in  the 
intestine  is,  however,  augmented  by  the  presence  of  zymo-excitors. 
The  ethereal  extract  of  the  bile  is  slightly  active  in  this  direction.  The 
bile  salts  are  very  active,  the  cholic  acids  being  the  potent  substances. 
Thus  the  presence  of  bile  can  be  shown  in  vitro  to  quadruple  the  velocity 
of  the  hydrolysis  of  a  constant  substrate  of  fat  acted  upon  by  a  constant 
mass  of  lipase.  This  constitutes  in  fact  the  best-known  illustration 
in  the  body  of  the  action  of  a  zymo-excitor.  Acting  under  these  cir- 
cumstances, despite  the  low  solubility  of  the  fats  and  the  dependence 
of  the  reaction  velocity  upon  the  attainment  of  a  proper  emulsion, 
in  actual  digestion  the  cleavage  of  fat  is  a  reaction  of  large  extent. 
Within  a  few  hours  a  hundred  grams  of  fat  may  be  entirely  split,  this 
accomplishment  being,  of  course,  the  united  work  of  the  intestinal 
and  the  pancreatic  lipases.  That  the  activation  and  zymo-excitation 
of  the  bile  are  not  indispensable  is  shown  by  the  excellent  digestion  of 
fats  to  be  noted  in  many  cases  of  complete  absence  of  the  bile  from  the 
intestine.  As  will  be  described  later,  the  bile  has  not  only  active  rela- 
tions to  the  cleavage  of  the  fats  by  lipase,  it  has  also  important  relations 
to  the  solubility  of  fats.  And  since  it  is  not  possible  in  vivo  to  separate 
these  two  factors  and  to  evaluate  them,  we  are  not  in  a  position  to 
state  to  which  of  the  actions  of  the  bile  the  loss  is  to  be  ascribed  in 
those  cases  in  which  the  absence  of  bile  carries  with  it  a  reduction  in 
the  digestion  of  fat.  Certain  it  is,  however,  that  in  vivo  the  pancreatic 
lipase  is  able  to  exhibit  a  proper  activation  and  a  satisfactory  accelera- 
tion of  the  hydrolysis  of  fats  in  the  absence  of  the  bile. 

The  lipase  of  the  pancreatic  juice  accelerates  the  hydrolysis  of  esters 
as  a  class,  not  only  the  higher  fats,  but  also  the  lower  esters  of  the 
natural  fatty  acid  series,  and  all  manner  of  complex  and  synthetic  esters. 


160  DIGESTION 

The  enzyme  is,  for  a  ferment,  very  stable,  the  vegetable  lipases  being 
probably  the  most  stable  of  all  ferments.  The  ferment  acts  well  in 
either  acid  or  alkaline  medium  of  moderate  concentration.  Accurate 
investigations  are  not  easily  carried  out,  since  with  the  progress  of 
the  hydrolysis  of  a  fat,  acid  is  being  constantly  set  free  to  combine 
with  alkali.  Rather  high  concentrations  of  the  product  (fatty  acid), 
are  tolerated,  even  in  the  case  of  the  more  highly  dissociated  lower 
fatty  acids.  In  fact,  up  to  a  certain  point,  it  is  a  question  if  the  fatty 
acid  does  not  indeed  contribute  an  auto-catalytic  influence  with  the 
result  of  increasing  the  velocity  of  cleavage.  The  ferment  is  fairly 
resistant  to  bacterial  action,  particularly  in  the  presence  of  fat.  Lipase 
may  be  found  in  the  normal  stools,  though  not  invariably.  This  find- 
ing, different  from  that  noted  for  the  fermentation  of  the  sugars,  is 
explained  in  part  by  the  fact  of  the  greater  resistance  of  the  ferment; 
in  part,  however,  by  the  fact  that  unaltered  substrate,  which  protects 
the  ferment  from  destruction,  is  always  present  in  the  stools.  The 
presence  of  lipase  in  the  stools  cannot  be  used  as  a  test  of  the  function 
of  the  pancreas,  since  the  succus  entericus  contains  a  lipase.  In  any 
event,  its  absence  from  the  stools  would  not  indicate  that  it  had  not 
been  secreted. 

Included  in  the  diet  are  many  complex  lipoids,  termed  phosphatids 
and  sterins,  the  chemical  constitution  of  which  will  be  described,  so 
far  as  that  is  possible,  on  another  page.  The  behavior  of  these  lipoids 
in  digestion  is  not  well  understood.  For  the  sterins  (cholesterols) 
the  present  idea  is  that  they  are  largely  rejected  with  the  feces.  It  is, 
however,  not  proper  to  state  that  they  cannot  be  and  are  not  resorbed. 
Though  they  are  very  insoluble  in  water,  they  are  to  a  slight  extent 
soluble  in  triolein,  and  thus  the  chemical  possibility  of  their  resorption 
is  established.  The  fate  of  the  phosphatids,  if  we  may  judge  them  at 
all  by  common  lecithin,  is  hydrolysis  through  the  action  of  the  lipase 
of  the  pancreatic  duct  and  intestine.  Beyond  that  we  know  nothing. 
Whether  the  components,  especially  the  glycerol-phosphoric  acid  and 
the  cholin,  are  utilized  in  the  body  following  their  resorption,  is  not 
known.  That  the  body  possesses  the  power  of  forming  glycerol-phos- 
phoric acid  from  the  two  components  is  known;  the  organism  is,  there- 
fore, not  dependent  upon  the  phosphatids  of  the  diet.  To  the  writer 
the  most  reasonable  assumption  is  that  the  body  forms  its  phosphatids 
de  novo,  and  is  in  no  way  dependent  upon  the  glycerol-phosphoric 
acid  and  cholin  of  the  diet. 

Chymosin. — Within  recent  years  it  has  been  demonstrated  that 
the  pancreatic  juice  is  able  to  coagulate  milk.  This  faculty  can  be 
shown  to  be  in  all  probability  independent  of  the  ferment  trypsin. 
The  properties  of  the  pancreatic  rennet  seem  to  be  identical  with 
those  of  the  gastric  rennet,  except  possibly  in  a  greater  sensitiveness 
to  acid  and  a  greater  resistance  to  alkali.  The  reaction  of  curdling  is 
accomplished  in  either  acid,  neutral  or  alkaline  reaction,  the  appear- 
ances and   properties  of  the  curd  differ  in  nowise  from  those  noted 


THE  PANCREAS  161 

in  curdling  by  gastric  chymosin.  There  is  one  difference  in  the  two 
secretions,  however:  the  gastric  juice  contains  more  rennet  than  does 
the  pancreatic  juice,  and  less  of  the  secretion  is  required  to  coagulate 
a  given  volume  of  milk.  The  function  is  obviously  non-operative  in 
ordinary  digestion,  since  after  the  action  of  the  gastric  juice  upon  milk 
no  further  coagulation  is  possible. 

Trypsin. — The  proteolytic  ferment  of  the  pancreatic  juice  is  termed 
trypsin.  It  is  secreted  in  an  inactive  state.  On  reaching  the  duodenum 
the  zymogen  becomes  activated  by  the  succus  entericus.  Since  it  can 
be  shown  that  this  property  of  activation  is  not  common  to  all  forms 
of  intestinal  secretion,  it  is  credited  to  a  special  substance  that  has 
been  named  enterokinase.  The  duodenal  mucosa  presents  enterokinase 
in  its  juice  only  following  the  discharge  of  the  inactive  pancreatic 
juice  into  the  duodenum.  In  other  words,  it  is  the  presence  of  the 
inactive  pancreatic  juice  (activated  juice  will  have  the  same  result) 
in  the  duodenum  that  stimulates  the  mucous  membrane  there  to  the 
secretion  of  the  enterokinase.  The  mere  presence  of  food  or  water 
or  even  of  boiled  pancreatic  juice  has  no  such  result.  No  enterokinase 
will  be  found  in  the  succus  entericus  of  an  animal  whose  pancreatic 
juice  is  discharged  outside  the  body.  This  enterokinase  activates  in 
direct  portional  to  its  mass,  and  is  to  be  regarded  as  a  catalyzer.  The 
reaction  of  the  activation  of  the  trypsinogen  is  a  reaction  of  hydrolysis, 
and  can  be  shown  to  be  an  autoreaction : 

Trypsinogen  +  water  =  trypsin 

The  enterokinase  accelerates  this  reaction.  While  on  the  one  hand 
the  secretion  of  the  pancreatic  juice  and  its  presence  in  the  duodenum 
is  the  sole  occasion  for  the  secretion  of  enterokinase,  the  activation 
of  trypsinogen  is  not  limited  to  enterokinase.  The  salts  of  calcium 
are  quite  active  activators,  and  it  is  to  its  calcium  content  that  the 
bile  owes  its  demonstrable  powers  of  activation.  Bacterial  products 
and  extracts  of  tissues  (apparently  of  any  of  the  internal  glands  or 
tissues)  are  also  activators.  Apparent ly,  therefore,  the  activation  of 
the  pancreatic  trypsin  would  occur  even  in  an  intestine  exhibiting  no 
secretion.  Under  normal  conditions  the  reaction  of  activation  is  one 
of  great,  rapidity.  Enterokinase  is  thermolabile,  but  soluble  in  alcohol. 
Trypsin  is  a  ferment  of  comparative  stability  and  of  great  activity. 
As  previously  described,  experiments  in  glass  would  seem  to  indicate 
certain  limitations.  The  early  stages  of  digestion  (decoagulation  and 
transformation  into  proteoses)  it  does  not  accomplish  as  rapidly  as 
does  pepsin;  egg  albumin  and  serum  albumin  are  digested  by  it  with 
difficulty,  and  some  of  the  proteins  of  the  connective-tissue  groups 
seem  entirely  resistant  to  it.  On  the  other  hand,  it  is  not  able  to 
complete  the  cleavage  of  the  resistant  polypeptid  nucleus,  and  to  set 
free  the  contained  amino-acids.  The  last  function  is,  however,  executed 
by  the  erepsin.  As  to  the  first-mentioned  limitations,  experience  in 
intestinal  digestion  without  gastric  juice  does  not  indicate  any  appre- 
11 


162  DIGESTION 

ciable  delay  or  limitation  in  the  digestion  of  proteins  under  such  cir- 
cumstances. All  of  the  work  of  the  gastric  digestion  of  protein  in  the 
stomach  is  easily  and  unnoticeably  accomplished  in  the  small  intestine. 
And  since  it  seems  clear  from  investigations  with  erepsin  that  it  can- 
not be  held  responsible  for  the  reactions  in  the  earlier  stages,  either 
the  limitations  of  trypsin  observed  in  experiments  in  vitro  do  not  hold 
in  the  intestine,  or  the  duodenum  must  secrete  another  proteolytic 
ferment.  For  the  latter  suggestion  some  experimental  work  may  be 
held  to  speak  in  a  provisional  manner.  It  will  for  the  present,  how- 
ever, be  safest  to  enlarge  our  concept  of  the  function  of  trypsin.  Apart 
from  the  proteins  of  the  connective-tissue  group,  all  the  chief  proteins 
of  plant  or  animal  origin  are  easily  digestible  by  trypsin.  The  secretion 
of  a  day  can  be  shown  to  be  capable  of  digesting  several  hundred  grams 
of  protein.  This  digestion,  shared  with  the  erepsin,  must  be  regarded 
as  a  most  thorough  one;  that  is,  all  the  protein  of  a  diet  is  digested 
at  least  to  the  polypeptid  stage,  the  larger  amount  passing  completely 
to  amino-acids.     (Cf.  page  47.) 

To  what  extent  quantitatively  the  cleavage  of  protein  in  digestion 
normally  proceeds,  is  impossible  of  accurate  determination.  On  the 
one  hand,  there  is  no  question  that  peptones  have  the  power  of  diffu- 
sion. Proteoses  and  peptones,  native  proteins  indeed,  seem  to  be 
resorbable  from  isolated  loops  of  intestine.  That  this  resorption, 
however,  is  not  simple  in  the  sense  of  a  parenteral  resorption,  is  shown 
by  the  fact  that  a  precipitin  reaction  is  not  established  by  such  intestinal 
resorption.  On  the  other  hand,  it  seems  clear  that  peptones  cannot 
be  used  as  building  stones  for  protein.  Even  should  peptones  be 
resorbed,  it  is  most  likely  that  they  would  be  split  within  the  intestinal 
wall.  Nitrogenous  equilibrium  and  the  formation  of  flesh  can  be 
accomplished  by  the  split  products  of  the  digestion  of  protein — amino- 
acids.  This  fact  is  obviously  in  itself  no  direct  proof  that  normally 
digestion  proceeds  thus  far.  The  data  bearing  upon  anaphylaxis  make 
it  certain  that  the  reaction  of  hydrolysis  proceeds  to  the  point  of 
obliteration  of  the  specific  biological  properties  of  protein.  Whether 
this  cleavage  occurs  within  the  lumen  or  partly  within  the  wall  of  the 
intestine  is  not  known.  There  are  observations  tending  to  connect 
the  sensitizing  property  of  native  protein  with  the  antipeptone  fraction. 
If  this  be  true,  protein  digestion  must  be  a  very  complete  one.  From 
the  point  of  view  of  the  syntheses  of  the  blood  proteins,  it  is  evident 
that  complete  or  nearly  complete  cleavage  of  the  protein  molecule  is 
necessary  to  make  possible  the  formation  of  the  blood  proteins  from 
the  diverse  proteins  of  the  diet.  Some  of  the  amino-acids  required 
in  the  synthesis  of  the  blood  proteins  are  in  the  last  resistant  fraction 
of  antipeptone,  and  it  cannot  be  believed  that  this  resistant  fraction 
is  a  unit  common  to  all  proteins;  it  too  is  a  biological  entity.  From 
every  point  of  view  we  are  led  to  the  assumption  that  in  the  digestion 
of  protein,  accomplished  finally  by  trypsin  and  erepsin,  the  cleavage  of 
the  protein  molecule  is  practically  complete. 


THE  PANCREAS  163 

The  conditions  of  favorable  action  of  trypsin  are  rather  wide.  It 
exhibits  a  notable  resistance  to  hydrochloric  acid,  which  enables  it  to 
resist  destruction  by  the  gastric  contents  pending  the  neutralization 
of  the  acid  by  the  pancreatic  alkali.  It  is  able  to  act  in  a  slightly  acid 
medium.  It  tolerates  rather  high  concentrations  of  alkali,  though  the 
reaction  optimum  can  be  shown  in  the  case  of  the  dog  to  be  about 
ttjwo  •  The  concentration  of  bacterial  organic  acids  in  the  normal 
intestinal  tract  does  not  inactivate  trypsin.  Such  high  concentrations 
of  hydrochloric  acid  as  are  sometimes  seen  in  exaggerated  instances  of 
hyperchlorhydria  would  certainly  operate  destructively  to  the  trypsin 
were  it  not  for  the  fact  that  in  such  cases  the  pancreatic  juice  is  in  a 
proportional  manner  excessively  alkaline,  so  that  in  the  end  the  reac- 
tion within  the  intestine  is  not  different  from  the  normal — there  is 
simply  more  sodium  chlorid  present.  The  favorable  action  of  alkali 
upon  the  process  of  digestion  by  trypsin  may  be  regarded  as  due  to 
combination  with  the  ferment.  The  enzyme  is  to  be  regarded  as  a  weak 
acid,  and  a  salt  with  the  alkali  would  be  subject  to  a  greater  dissociation 
than  the  acid  itself,  thus  leading  to  a  greater  catalytic  activity. 

Trypsin  is  often  present  in  the  stools.  This  is  again  a  fact  to  be 
remembered  in  connection  with  rectal  alimentation.  When  absent, 
this  is  probably  the  result  of  bacterial  putrefaction.  In  the  case  of 
the  destruction  of  amylase,  maltase,  and  lipase  it  is  possible  to  picture 
them  as  digested  by  the  trypsin  and  erepsin.  In  the  case  of  these, 
however,  bacterial  action  is  to  be  invoked  in  explanation  of  their 
destruction.  One  factor  of  importance  in  determining  the  occurrence 
of  active  trypsin  in  the  feces  is  the  period  of  retention  of  the  feces  in 
the  colon,  which  varies  in  different  individuals  from  twenty-four  to 
sixty  hours,  rarely  to  ninety  hours.  The  longer  the  retention  of  the 
feces  in  the  colon,  the  more  opportunity  is  afforded  bacteria  to  destroy 
the  ferment. 

The  Pathology  of  Pancreatic  Secretion. — The  variations  in  the  secre- 
tion of  the  pancreatic  gland,  under  systematic  classification,  would 
fall  under  two  heads — excessive  secretion  and  deficiency  or  total  lack 
of  secretion. 

Excessive  Secretion. — Excessive  secretion  could  involve  the  water, 
the  ferments,  or  the  alkali.  Of  the  total  secretion  of  the  pancreas  so 
little  is  known  that  we  lack  a  norm  with  which  an  accidentally  measur- 
able secretion  could  be  contrasted.  That  such  a  state  exists  as  a  hyper- 
secretion of  the  pancreas,  comparable  with  hypersecretion  of  the 
stomach,  is  not  known.  Judged  by  the  known  facts  for  the  parotid 
gland,  such  a  state  could  result  from  abnormal  reactions  in  the  nervous 
connections  and  might  result  also  as  an  acute  condition  from  inflamma- 
tion. A  prolonged  excessive  secretion  would  be  a  hypersecretion  of 
water,  and  not  of  the  ferments  and  alkali,  as  is  true  of  the  chronic 
hypersecretions  of  the  parotid  gland.  Excessive  secretion  of  alkali, 
except  as  reciprocal  to  hyperchlorhydria  of  the  stomach,  is  unlikely 
if  not  impossible.     While  it  is  possible  to  withdraw  cations  through 


164  DIGESTION 

the  agency  of  acid  introduced  into  the  system,  there  is  no  known 
possibility  of  the  spontaneous  elimination  of  alkali. 

Deficient  Secretion. — Much  more  likely  to  occur  is  deficient  secretion. 
From  what  is  known  of  the  diseases  of  the  stomach  and  salivary  glands, 
chronic  disease  involving  the  secretory  apparatus  might  be  expected 
to  result  in  a  reduction  of  the  secretion.  But  the  chronic  diseases  of 
the  pancreas  are  concerned  largely  with  sclerosis,  and  usually  involve 
the  acini  to  but  slight  extent.  Acute  disease  of  the  pancreas  attended 
with  destruction  of  tissue,  as  in  septic  and  hemorrhagic  pancreatitis, 
surely  leads  to  pronounced  reduction  or  complete  abolition  of  the 
secretion.  But  there  is  no  simple  way  of  measuring  the  pancreatic 
secretion  except  by  observation  of  the  functions  of  digestion  of  fats 
and  protein,  and  in  this  way  only  in  a  conjectural  manner.  Such 
observations,  revealing  sometimes  profound  reduction  in  the  diges- 
tions, have  been  made  in  instances  of  chronic  disease;  the  tests  are 
out  of  the  question  in  acute  diseases  of  the  pancreas.  With  intact 
functions  of  the  stomach,  bile  and  intestinal  juice,  the  complete  cessa- 
tion of  pancreatic  secretion  might  lead  to  no  reduction  in  the  efficiency 
of  digestion.  Low  indicanuria  was  once  supposed  to  suggest  deficient 
pancreatic  digestion;  this  is  not  true  in  fact,  and  the  suggestion  is 
faulty  in  theory,  since  the  tryptophan  from  which  the  bacteria  form 
the  indican,  is  set  free  by  erepsin  as  well  as  by  trypsin.  Cessation  of 
pancreatic  secretion,  or  complete  obstruction  of  the  pancreatic  duct 
or  ducts,  is  often  followed  by  some  distinct  reduction  of  the  powers 
of  digestion,  involving  most  the  fats.  When  such  a  patient  is  placed 
upon  a  known  diet,  it  is  found  that  the  residual  nitrogen  of  the  stools 
is  much  increased,  from  possibly  10  per  cent,  of  the  input  up  to  30 
per  cent.;  in  pancreatic  diabetes  the  azotorrhea  may  be  still  higher. 
If  the  subject  is  on  a  minimal  protein  ration,  this  may  not  be  at  all 
apparent,  but  can  be  provoked  by  placing  the  subject  upon  a  higher 
protein  input.  With  a  known  fat  input  the  residual  neutral  fat  of  the 
stools  may  exhibit  a  pronounced  increase.  This  fat  will  usually  be 
neutral  fat,  indicating  failure  of  enzymic  cleavage  and  not  failure 
of  resorption.  If  the  subject  be  on  a  low  fat  ration,  this  may  not  be 
apparent,  but  can  be  provoked  by  the  ingestion  of  amounts  of  fat  that 
are  larger  though  well  within  the  normal  range.  It  is  remarkable  in 
experiments  with  dogs,  how  frequently  a  normal  digestion  will  be 
maintained  in  the  properly  fed  animal  following  ligation  of  the  pan- 
creatic ducts;  but  if  the  gland  be  extirpated,  the  results  upon  digestion 
are  often  much  more  pronounced.  Applying  these  results  to  human 
beings,  it  may  be  said  that  a  pronounced  reduction  in  the  cleavage 
of  fat  and  in  the  resorption  of  protein  suggests  strongly  the  cessation 
of  pancreatic  secretion  or  obstruction  of  the  ducts;  but  a  normal  diges- 
tion does  not  prove  normal  secretion  or  patulous  pancreatic  ducts. 
Different  animals  react  differently,  thus  the  rabbit  reacts  to  the  absence 
of  pancreatic  juice  much  less  than  the  dog.  This  warns  us  to  apply  to 
man  with  circumspection  the  knowledge  obtained  by  tests  with  animals. 


THE  PANCREAS  165 

Within  recent  years  methods  have  been  developed  to  secure  duodenal 
contents  from  human  beings  for  the  purpose  of  direct  determination 
of  the  presence  of  pancreatic  juice.  Following  the  ingestion  of  a  meal 
rich  in  fat,  regurgitation  of  duodenal  contents  into  the  stomach  occurs 
with  such  frequency  as  to  afford  a  basis  of  examination.  Methodically 
preferable,  however,  is  direct  sampling  of  the  duodenal  contents  by 
means  of  the  Einhorn  bucket.  In  the  nature  of  things,  the  evidence 
to  be  obtained  from  a  direct  examination  of  duodenal  contents  must 
surpass  any  indirect  method  of  estimation  of  the  presence  of  the 
pancreatic  enzymes  in  the  intestinal  tract. 

Reduction  or  cessation  of  the  alkali  secretion  of  the  pancreas  must 
be  regarded  as  strictly  reciprocal  to  the  secretion  of  hydrochloric  acid 
in  the  stomach.  In  achlorhydria,  there  must  be  practically  an  absence 
of  alkalinity  in  the  pancreatic  juice.  The  influence  of  this  upon  the 
processes  of  intestinal  digestion  can  only  be  conjectured.  Since,  how- 
ever, it  is  well  known  that  achlorhydria  need  carry  with  it  no  disturbance 
of  digestion  at  all,  it  is  clear  that  the  pancreatic  alkali  is  dispensable 
in  the  intestine.  The  figures  given  for  the  optimal  reactions  of  the 
several  ferments  operating  within  the  intestine  indicate  how  little  alkali 
is  required  for  them.  Test-tube  experiments  indicate  also  how  little 
alkali  is  necessary  to  produce  good  emulsifications  with  neutral  fats 
and  fatty  acids,  especially  in  the  presence  of  bile.  That  higher  con- 
centrations of  alkali  increase  the  solubility  of  the  fatty  acids  is,  of 
course,  true;  but  the  surface  of  resorption  is  so  large  that  apparently 
the  intestine  can  complete  absorption  from  low  concentration.  In  the 
case  of  obstruction  of  the  pancreatic  duct,  if  the  secretion  of  hydro- 
chloric acid  in  the  stomach  be  continued  in  the  usual  manner,  the 
alkali  secretion  that  normally  passes  through  the  pancreas  must  be 
eliminated  by  the  small  intestine. 

Activation  of  the  ferments  of  the  pancreas  within  the  organ,  in 
particular  of  lipase  and  trypsin,  would  have  the  result  of  self-digestion 
of  the  gland  and  possibly  of  the  surrounding  tissues.  There  is  no  ques- 
tion that  this  does  occur;  this  and  septic  infection  probably  comprise 
nearly  all  the  cases  of  acute  pancreatitis.  The  activation  of  the  ferments 
within  the  ducts  may  be  caused  by  bile,  hydrochloric  acid,  intestinal 
juice,  and  possibly  also  by  bacterial  products.  Just  as  septic  infection 
will  be  added  to  self-digestion,  so  self-digestion  may  be  added  to  septic 
infection.  The  products  of  such  self-digestion  are  very  toxic.  If  into 
the  sterile  peritoneal  cavity  of  a  dog,  the  sterile,  freshly  macerated 
pancreas  of  a  second  dog  be  introduced,  the  result  will  be  death  within 
twenty-four  hours  as  a  rule.  This  illustrates  what  will  happen  if  the 
self-digestion  occurs  within  the  animal's  own  pancreas,  except  that 
resorption  of  the  toxic  products  will  in  such  a  case  be  slower  and  death 
longer  deferred.  This  experiment  indicates  the  necessity  of  drainage 
in  such  a  case  in  man ;  how  one  who  survives  such  an  attack  with  opera- 
tion is  to  continue  life,  will  depend  upon  the  extent  of  destruction  of 
the  pancreas  and  upon  other  circumstances. 


166  DIGESTION 

One  difficulty,  it  must  be  pointed  out,  lies  inherent  in  the  investiga- 
tion of  abnormalities  of  pancreatic  secretion.  As  will  be  later  described, 
the  pancreas  possesses  a  most  important  inner  function.  Derangements 
in  this  inner  function  lead  to  profound  disturbances  in  metabolism, 
i.  e.,  diabetes.  The  separation  of  these  from  the  effects  of  digestive 
derangements  that  might  result  from  suspension  of  pancreatic  secre- 
tion (or  obstruction  of  the  ducts)  may  be  impossible.  A  lesion  might 
involve  only  one  function,  secretory  or  internal;  a  lesion  might  affect 
both  functions.  Diabetics  usually  present  normal  intestinal  digestion; 
in  some  cases  it  is  seriously  disturbed.  Obviously  the  relations  may  be 
obscure  and  a  clear  picture  of  the  facts,  morphological  and  chemical, 
may  not  be  obtainable.  The  experimental  data  are  contradictory. 
On  the  one  hand  are  reports  that  indicate  that  ligation  of  the  ducts 
leads  to  little  or  no  injury  to  the  processes  of  digestion.  One  explana- 
tion that  was  suggested  to  elucidate  this  result  was  that  the  ferments 
were  resorbed  into  the  circulation,  carried  to  the  intestine,  and  eliminated 
into  the  lumen,  there  to  meet  the  food.  This  explanation,  however, 
fell  to  the  ground  as  soon  as  it  was  found  that  the  identical  result  was 
secured  in  the  dog  with  pancreatic  fistula,  in  which  the  intestine  was 
deprived  of  its  pancreatic  ferments  completely.  Extirpation  of  the 
pancreas  in  these  cases  was  followed  by  profound  reduction  in  the 
processes  of  digestion,  i.  e.,  in  some  internal  way  the  pancreas  acts 
upon  the  processes  of  digestion.  In  harmony  with  this  interpretation  is 
the  fact  that  feeding  with  pancreas  or  the  injection  into  the  duodenum 
of  pancreatic  juice,  has  little  result  on  digestion  in  animals  that  have 
suffered  extirpation  of  the  gland,  as  in  this  way  only  the  externally 
active  substances  of  the  gland  are  introduced.  In  the  rabbit  and 
apparently  in  the  dog,  it  is  possible  to  have  the  pancreas  atrophy  after 
ligation  of  the  ducts  with  little  or  no  disturbance  of  digestion,  at  least 
with  no  more  than  a  reduction  in  the  limit  of  assimilation  of  sugar. 
In  such  a  rabbit,  autopsy  has  indicated  the  complete  atrophy  of  the 
acini,  with  retention  of  the  islands  of  Langerhans.  On  the  other  hand, 
opposed  to  all  these  findings,  are  the  facts  that  not  seldom  in  dogs 
with  diabetes  following  removal  or  atrophy  of  the  pancreas,  the  diges- 
tive processes  are  very  well  maintained.  And  in  some  dogs,  in  whom 
a  portion  of  the  pancreas  has  been  retained,  digestion  is  greatly  dis- 
turbed. These  results  are  interpreted  to  mean  that  the  sole  influence 
the  pancreas  has  on  the  processes  of  digestion  is  through  the  pancreatic 
juice;  and  whether  digestion  in  the  absence  of  this  juice  is  well  or  poorly 
accomplished,  depends  upon  the  powers  of  adaptation  of  the  other 
secretions  of  the  digestive  tract. 


THE   SECRETIONS    OF   THE   INTESTINES 

The  secretions  of  the  intestine  contain  substances  of  four  groups: 
ferments  and  allied  bodies;  salts;  end  products  of  metabolism;  and 


THE  SECRETIONS  OF  THE  INTESTINES  167 

proteins.  The  proteins  belong  to  the  mucin  group  and  are  secreted, 
as  in  the  stomach,  in  considerable  amounts,  probably  as  much  as  10 
to  15  grams  per  day.  Their  function  is  to  aid  in  the  processes  of  emul- 
sification  of  the  intestinal  contents.  End  products  of  metabolism  are 
here  eliminated  in  but  small  amounts;  a  consideration  of  these  will 
be  undertaken  in  another  place.  The  salts  eliminated  by  the  intestine 
include  all  those  subject  to  elimination  by  the  body,  but  concern 
especially  the  salts  of  iron,  lime,  and  phosphoric  acid.  In  the  elimina- 
tion of  chlorids  and  sulphates,  and  of  the  cations  sodium,  potassium, 
and  ammonium,  elimination  by  the  intestine  seems  to  be  in  a  sense 
incidental.  But  in  the  elimination  of  iron,  calcium  and  phosphoric 
acid,  the  intestinal  elimination  is  specific.  The  larger  fraction  of  ferric 
elimination  is  accomplished  by  the  small  intestine,  and  of  the  calcium 
and  phosphoric  acid,  half  is  frequently  eliminated  here. 

The  small  intestine  displays  apparently  two  types  of  secretion — 
one  associated  with  digestion,  one  independent.  When  the  stomach 
of  the  dog  is  empty  and  the  dog  is  starving,  a  periodic  secretion  of 
succus  entericus  occurs  about  every  two  hours.  The  secretion  is  rich 
in  mucin  and  poor  in  ferment.  It  is  this  secretion  (including  the  bile) 
that  forms  the  stools  in  starvation.  When  now  food  is  in  the  stomach, 
this  periodic  secretion  seems  to  be  inhibited.  When  food  is  discharged 
from  the  stomach  into  the  intestine,  rapid  secretion  of  strongly  enzymic 
juice  is  inaugurated.  In  this  digestive  secretion  several  factors  seem 
to  be  operative;  the  presence  of  the  bulk  of  the  chyme  (distention) 
in  the  duodenum;  the  action  of  the  pancreatic  juice  and  possibly  the 
action  of  secretin,  as  in  the  case  of  the  pancreas.  The  bile  has  apparently 
no  effect  upon  the  secretion  of  the  intestine,  nor  has  the  hydrochloric 
acid  any  demonstrable  direct  effect.  The  secretion  of  the  intestine  is 
most  marked  in  the  duodenum,  and  descending  the  tract  lessens. 

Not  a  little  alkali  is  eliminated  in  the  succus  entericus.  Contrasted 
even  with  the  amount  eliminated  in  the  pancreatic  duct,  the  fraction 
is  considerable.  Although  no  analyses  are  possible,  it  is  clear  that  it 
must  be  largely  in  the  state  of  bicarbonate.  It  is  sufficient  to  be  of 
determining  importance  in  the  solution  and  resorption  of  fats  and 
their  products  of  digestion,  as  is  to  be  witnessed  in  those  not  infrequent 
instances  in  which,  with  the  exclusion  of  the  pancreatic  secretion  from 
sthe  intestine,  the  digestion  and  resorption  of  fats  proceeds  in  a  fairly 
or  indeed  entirely  normal  manner.  It  is,  however,  possible  that  in 
the  event  of  non-secretion  by  the  pancreas,  the  alkali  elimination  of  the 
succus  entericus  is  increased;  certainly  this  is  to  be  taken  for  granted 
in  the  event  of  normal  secretion  of  hydrochloric  acid  in  the  stomach  in 
such  cases.  In  infants  the  presence  of  abnormal  amounts  of  acid  in  the 
intestine  may  result  in  the  elimination  of  excesses  of  alkali,  and  in 
the  consequent  depletion  of  the  cations  of  the  body. 

Very  little  water  is  eliminated  by  the  intestine,  probably  not  over 
200  c.c.  per  day.  The  secretions  are  not  watery,  but  thick  and  viscid 
under  normal  conditions.  When  one  contrasts  the  water  content  of 
the  normal  feces  with  the  amount  of  water  that  enters  the  duodenum, 


168  DIGESTION 

the  water  ingested  in  food  and  beverage,  the  water  secreted  by  the 
salivary  glands,  by  the  stomach,  by  the  pancreas  and  in  the  bile,  the 
extent  of  water  resorption  by  the  intestine  becomes  clear.  We  may 
approximate  this  water  as  amounting  to  some  six  liters  per  day.  This 
is  the  water  that  serves  as  the  solvent  for  the  products  of  digestion  in 
their  resorption.  The  dependence  of  the  normal  processes  of  diges- 
tion and  resorption  upon  this  volume  of  water  in  the  intestine  must 
be  very  direct.  And  the  diet  fad  that  attempts  to  restrict  water  input 
to  the  lowest  possible  limits  is  operating  contrary  to  sound  physiological 
sense. 

Ferments  of  Intestinal  Juice. — The  succus  entericus  contains  eight 
ferments,  the  intestine  being  the  one  tissue  that  forms  all  the  different 
ferments  of  the  alimentary  tract.  These  are  amylase,  maltase,  invertase, 
lactase,  emulsin,  erepsin,  lipase,  and  chymosin.  It  is  the  occurrence 
of  all  these  ferments  in  the  secretion  of  the  intestine  that  explains  the 
unquestioned  fact  that  with  the  removal  of  the  functions  of  the  salivary 
glands,  stomach  and  pancreas  from  the  processes  of  digestion,  these 
can  under  favorable  conditions  be  fully  accomplished  by  the  small 
intestine  alone.  It  is  incorrect  to  state  that  with  the  loss  of  the  men- 
tioned secretions,  one  or  all,  the  small  intestine  vicariously  assumes 
their  functions;  in  truth,  it  possesses  all  these  faculties  naturally  and 
exercises  them  normally.  We  possess,  therefore,  in  digestion  what  in 
the  technical  trades  would  be  called  duplicate  plants.  Of  the  advantage 
of  this  duplicate  installation,  the  study  of  pathology  furnishes  many 
illustrations. 

Of  these  ferments  little  may  be  stated  in  a  definite  sense.  It  is  so 
difficult  to  secure  succus  entericus  for  study  and  so  difficult  to  exclude 
bacterial  processes,  that  investigations  have  been  few  and  the  results 
have  been  meagre.  The  rennet,  lipase,  and  erepsin  seem  to  be  secreted 
only  in  the  very  uppermost  portion  of  the  tract,  in  the  duodenum  and 
upper  jejunum;  the  amylase  and  the  ferments  for  the  disaccharids, 
however,  seem  to  be  secreted  also  in  the  ileum.  None  are  secreted 
in  the  colon.  Concerning  the  properties  of  the  amylase  and  maltase 
we  know  nothing  that  would  distinguish  them  from  the  amylase  and 
maltase  of  the  pancreatic  juice.  There  is  a  form  of  dyspepsia  known 
as  intestinal  fermentative  dyspepsia,  assumed  to  be  due  to  defective 
digestion  of  starch,  the  result  of  defective  action  of  the  intestinal 
amylase;  it  is  not  clear  how  the  relation  of  the  pancreatic  amylase  is 
to  be  excluded.  The  invertase  and  lactase  are  ferments  peculiar  to 
the  intestine,  as  is  also  probably  the  emulsin,  whose  importance  is 
greater  to  the  pharmacologist  than  to  the  physiologist.  The  invertase, 
which  splits  cane  sugar,  is  an  active  ferment  and  in  the  amounts  secreted 
per  day  is  able  to  hydrolyse  several  hundred  grams  of  sugar.  The  inver- 
tase of  bacteria  and  yeasts  are  usually  very  sensitive  to  bacterial  action, 
a  quality  evidently  not  shared  by  the  intestinal  invertase.  The  lactase 
is  usually  not  a  prominent  ferment  in  the  intestinal  juice,  since  it  has 
been  often  missed.  It  is  most  easily  demonstrated  in  young  animals. 
The  intestinal  juice  of  adult  herbivora  lacks  it,  while  it  is  sometimes 


THE  SECRETIONS  OF  THE  INTESTINES  169 

present  in  the  intestinal  juice  of  adult  carnivora  and  in  man.  It  is 
absent  at  all  ages  in  reptiles  and  birds.  The  rennet  is  secreted  only 
in  the  upper  duodenum,  is  not  prominent,  and  can  be  easily  overlooked. 
The  lipase  is  a  moderately  active  ferment;  the  bile  seems  not  to  be 
necessary  to  its  activation. 

The  erepsin  is  a  peptolytic  ferment  that  is  especially  prominent  in 
the  cleavage  of  peptone  and  polypeptids  into  the  amino-acids,  i.  e., 
it  operates  in  the  lower  part  of  the  scale  of  the  hydrolysis  of  protein. 
When  a  protein  is  submitted  to  prolonged  digestion  by  trypsin,  it  is 
found  that  from  10  to  20  per  cent,  of  the  nitrogen  remains  partially 
hydrolysed,  in  two  fractions  of  resistant  polypeptids — one  the  so-called 
abiuret  peptone  and  the  other  a  fraction  of  diamido-acids  combined 
with  monamino-acids.  These  groups  erepsin  is  able  to  hydrolyse. 
In  the  test-tube  erepsin  is  able  to  digest  casein,  fibrin,  protamins, 
and  histons,  but  has  little  effect  upon  the  common  native  albumins, 
globulins,  and  muscle  proteins.  It  is  also  able  to  digest  all  the  synthetic 
polypeptids  formed  of  naturally  occurring  amino-acids.  It  is  appar- 
ently active  when  secreted.  Erepsin  acts  only  at  neutral  or  alkaline 
reaction,  and  in  the  test-tube  behaves  as  though  very  sensitive.  All 
this  to  the  contrary,  however,  the  erepsin  is  able  alone  to  carry  on  the 
total  digestion  of  protein  in  the  body.  This  it  is  able  to  do  only  under 
favorable  conditions,  and  it  is  possible  that  digestion  could  not  be 
indefinitely  maintained  with  this  ferment  alone.  The  superimposed 
digestion  of  protein  by  pepsin,  trypsin,  and  erepsin  yields  by  far  the 
greatest  velocity  of  reaction,  though  digestion  by  trypsin-erepsin  is  not 
greatly  inferior. 

The  enterokinase  of  the  succus  entericus  was  described  in  connection 
with  the  activation  of  trypsin. 

Exogenous  Ferments. — The  foods  consumed  in  a  raw  state  contain 
ferments  of  different  kinds.  The  bacteria  of  the  alimentary  tract 
likewise  contain  ferments.  Have  these  any  role  in  digestion?  For 
the  carnivorous  animal  and  for  man,  probably  not.  The  velocity  of 
the  processes  of  autolysis  are  so  low  that  during  the  period  of  time 
concerned  in  digestion  little  could  be  accomplished.  The  fermenta- 
tive action  of  bacteria  is  much  more  pronounced.  Plants  contain 
amylase,  invertase,  and  maltase ;  many  also  lipase.  Much  more  promi- 
nent, however,  are  usually  the  alcoholic  and  acetous  fermentations; 
and  were  the  amylase,  maltase,  and  invertase  to  act  with  a  notable 
velocity,  the  sugar  formed  would  fall  a  prey  to  these  fermentations 
rather  than  be  absorbed.  The  bacterial  fermentation  of  fats  is  usually 
very  slow.  The  bacterial  fermentations  of  protein  are  rather  of  the 
nature  of  putrefaction  than  of  simple  hydrolysis,  of  which  products 
are  available  for  use  following  resorption.  In  any  event,  the  putre- 
factive processes  are  very  slow  compared  with  the  velocities  of  the 
processes  of  proteolytic  digestion.  It  may  be  regarded  as  certain, 
therefore,  that  in  man  the  activities  of  the  ferments  contained  in  the 
foods  or  elaborated  in  the  alimentary  tract  by  bacteria  do  not  contrib- 
ute to  the  chemical  processes  of  digestion  to  any  appreciable  degree. 


170 


DIGESTION 


In  the  case  of  herbivora,  however,  the  facts  are  different.  The  diges- 
tion of  the  grasses  and  coarse  plants,  especially  of  the  cellulose  they 
contain,  is  to  some  extent  aided  by  the  preformed  ferments  and  by  the 
action  of  bacteria.  While  it  is  true  that  the  intestinal  secretions  of 
herbivora  are  able  to  hydrolyse  cellulose,  the  bacterial  ferments  are 
surprisingly  active  in  this  direction.  To  what  extent  they  contribute 
in  the  digestion  of  this  extremely  resistant  substance  can  only  be  con- 
jectured; but  the  action  is  not  to  be  questioned.  In  man  the  digestion 
of  cellulose  is  practically  nil. 

In  carcinoma  of  the  stomach,  in  the  stage  of  ulceration,  a  ferment 
of  trypsin  type  is  found  in  the  stomach,  evidently  the  secretion  of  the 
neoplasm.  This  ferment  is  able  to  split  peptones,  and  tyrosin  and 
tryptophan  are  quickly  set  free.  It  is  also  able  to  split  synthetic 
polypeptids,  as  glycyl-tryptophan.  It  operates  at  neutral,  faintly 
acid,  or  alkaline  reaction.  Whether  this  ferment  be  different  from  the 
common  type  of  intracellular  trypsin  is  not  known.  If  it  is  present 
early  in  carcinoma,  it  is  possible  that  it  may  become  a  sign  of  decided 
diagnostic  value. 

THE   BILE 

The  bile  represents  the  mixed  secretions  of  the  liver  cells,  the  lining 
cells  of  the  biliary  ducts,  and  the  lining  cells  of  the  gall-bladder.  It 
is  to  be  regarded  partly  as  a  secretion,  in  part  as  an  elimination. 
It  is  a  continuous  secretion,  persisting  during  inanition,  presenting, 
however,  periods  of  increase  following  the  ingestion  of  food,  and  in 
part  dependent  upon  the  character  of  the  diet.  The  amount  of  secre- 
tion probably  varies  to  some  extent,  though  not  susceptible  of  measure- 
ment except  in  the  event  of  an  external  fistula  of  the  common  bile 
duct,  under  which  circumstances,  however,  the  secretion  may  display 
marked  abnormalities.  The  total  amount  may  be  judged  to  vary  from 
500  to  1000  c.c.  per  day.  There  is  a  continuous  secretion  of  bile.  Under 
the  influence  apparently,  of  secretin,  a  larger  flow  of  bile  occurs  during 
the  period  of  intestinal  digestion.  The  nitrogen  and  sulphur  content 
of  the  bile  rise  following  the  digestion  of  a  meal  rich  in  protein.  The 
secretion  of  bile  continues  during  starvation,  though  to  less  extent. 
The  reaction  is  alkaline,  due  to  traces  of  carbonate;  on  titration  it 
gives  the  appearance  of  a  much  greater  alkalinity,  due  to  the  presence 
of  bicarbonates.  The  general  composition  may  be  seen  from  the  table, 
a  composite  of  several  analyses  of  human  bile,  taken  from  the  ducts 
of  the  liver.    The  figures  are  in  one  thousand  parts. 


Water  . 

Solids    .      . 

Protein 

Biliary  salts 

Pigments    . 

Lipoids 

Cholesterol 

Inorganic  salts 

Diverse  organic  substances 


950.0  to  975 

25.0  to 

50 

3.0  to 

5 

8.0  to 

20 

1.0  to 

1 

0.5  to 

1 

0.5  to 

1 

0.5  to 

1 

0.5  to 

1 

THE  BILE  171 

The  bile  of  the  hepatic  ducts  is  much  richer  in  water  than  the  bile 
of  the  gall-bladder,  where  inspissation  occurs  and  mucus  and  choles- 
terol are  added.  The  alterations  are,  however,  more  than  thus  stated. 
The  solids  of  liver-duct  bile  average  about  3  per  cent.;  the  solids  of 
gall-bladder  bile  run  from  10  to  17  or  even  20  per  cent.  As  the  bile 
is  concentrated  by  inspissation  in  the  gall-bladder,  the  inorganic  salts 
are  in  part  absorbed,  so  that  the  gall-bladder  bile  is  poorer  in  inorganic 
salts  and  richer  in  organic  solids  than  is  the  liver-duct  bile.  Of  the 
total  solids  of  liver-duct  bile,  one-fourth  to  one-half  are  inorganic 
salts;  of  the  total  solids  of  gall-bladder  bile  only  4  to  6  per  cent,  are 
inorganic  salts.  The  biliary  salts  take  part  in  a  curious  lesser  circula- 
tion; a  small  fraction  is  absorbed  from  the  intestine,  carried  in  the 
portal  circulation  to  the  liver,  to  be  again  eliminated  in  the  bile.  It 
is  regarded  as  certain  that  the  biliary  acids  and  pigment  are  formed 
in  the  body  exclusively  in  the  liver. 

There  are  two  proteins  in  human  bile,  a  mucin  and  a  nucleoproteid, 
the  latter  being  present  in  larger  amount.  The  mucin  is  probably 
secreted  by  the  lining  cells  of  the  bile  ducts;  the  nucleoproteid  is 
secreted  by  the  lining  cells  of  the  gall-bladder.  The  bile  of  herbivora 
contains  nucleoproteid  only. 

Sulphur  Compounds  in  the  Bile. — The  richness  of  the  bile  in  sulphur 
compounds  impressed  the  earliest  observers.  The  total  content  of 
sulphur  runs  from  2  to  5  per  cent.,  according  to  the  animal,  with 
moderate  individual  variations.  The  biles  of  man,  primates,  swine, 
kangaroo,  and  hippopotamus  present  low  values;  the  bile  of  the  common 
herbivora  yield  medium  values;  the  highest  values  are  found  in  the 
bile  of  geese,  canines,  marine  animals,  and  some  fishes.  The  total 
sulphur  content  and  the  taurin  run  parallel.  Human  bile  from  the 
gall-bladder  contains  from  2.5  to  5  per  cent.  The  bile  flowing  from 
a  fistula  of  the  gall-bladder  has  been  found  free  of  organic  sulphur,  a 
markedly  pathological  condition.  There  is  no  relation  between  the  diet 
of  a  species  and  the  sulphur  content  of  the  bile;  the  diet  and  bile  of 
fishes  are  both  rich  in  sulphur,  but  the  carnivorous  animals,  whose 
diet  is  rich  in  sulphur,  have  often  less  sulphur  in  the  bile  than  is  to  be 
noted  in  herbivora  whose  diet  is  poor  in  sulphur.  The  sulphur  com- 
pounds in  the  bile  are  of  four  types:  preformed  sulphates;  ethereal 
sulphates;  sulphophosphorized  lipoids,  and  taurin  and  allied  com- 
pounds. Preformed  sulphates  are  present  only  in  traces.  Ethereal 
sulphates  are  contained  in  all  biles,  the  amounts  running  from  5  to 
15  per  cent,  of  the  total  sulphur.  They  yield  no  phenols  on  distilla- 
tion, thus  resembling  the  lesser  fraction  of  human  urinary  conjugated 
sulphates.  It  is  known  that  ethereal  sulphates  are  conjugated  in  the 
liver;  apparently  a  fraction  passes  into  the  bile,  the  larger  fraction 
into  the  venous  circulation.  Possibly  the  amount  in  the  bile  may 
stand  in  some  relation  to  the  intensity  of  intestinal  putrefaction.  The 
sulphophosphorized  lipoid  is  present  in  but  a  trace,  it  is  soluble  in 
alcohol  and  ether,  free  from  carbohydrate  but  yet  reduces  metallic 


172  DIGESTION 

salts,  contains  phosphorus  and  nitrogen  as  well  as  sulphur,  thus  a 
sulphophosphatid  of  unknown  constitution  and  derivation. 

Taurin. — The  last  and  the  most  important  sulphur  compound  in 
the  bile  is  the  taurin.  Human  bile  contains  two  so-called  biliary  acids, 
combinations  of  cholic  acid  with  glycocoll  and  taurin  respectively, 
eliminated  as  salts  of  sodium,  calcium,  and  potassium.  Taurin  is 
present  in  the  bile  of  practically  all  mammals,  reptiles,  birds,  and 
fishes.  In  certain  fishes  no  taurin  is  to  be  found,  instead  are  complex 
esters,  sulphocholesterols,  which  take  its  place.  While  taurin  is,  there- 
fore, a  substance  of  almost  universal  occurrence  in  bile,  quantitatively 
in  most  biles  the  amount  is  not  large,  and  the  glycocholate  forms 
the  larger  fraction  of  the  biliary  acids.  In  the  polar  bear,  the  dog, 
some  fishes,  and  in  the  goose  the  bile  is  practically  free  of  glycocholic 
acid,  i.  e.,  the  amount  of  taurin  being  high  and  the  amount  of  cholic 
acid  being  low;  the  taurin  is  present  in  amount  sufficient  to  combine 
with  all  the  cholic  acid.  The  chemical  fact  seems  to  be  that  glyco- 
cholic acid  is  found  only  when  cholic  acid  is  formed  in  the  liver  in 
excess  of  the  taurin,  which  is  the  case  except  in  the  instances  mentioned. 
In  man  the  ratio  of  glycocholate  to  taurocholate  varies  from  5  —  10  :  1. 

Cholic  acid  has  the  elementary  formula  C24H40O5.  Closely  related 
to  it  are  two  companion  substances  present  in  traces  in  many  biles, 
choleic  acid  (C24H40O4),  and  fellic  acid  (C23H40O4),  equally  obscure  in 
chemical  composition.  The  separation  of  the  cholic  acid  from  the 
glycocoll  and  taurin  is  a  simple  act  of  hydrolysis.  Thus  for  taurocholic 
acid: 

C26H45NS08  +  H20  =  C2H7NS03  +  C24H40O5. 

Cholic  acid  is  known  to  be  a  monobasic  alcoholic  acid,  containing  two 
primary  and  two  secondary  alcoholic  groups.  Since  it  has  been  shown 
to  be  a  derivative  of  cholesterol,  known  facts  for  other  derivatives  of 
cholesterol  and  the  stated  facts  for  cholic  acid  suggest  as  the  probable 
constitution  the  following: 

(CH2OH)2.C18H27.COOH 
H2C<^CHOH 
CHOH 

Cholic  acid  is  formed  in  the  body  only  in  the  liver,  and  its  conjugations 
with  glycocoll  and  taurin  are  so  far  as  known  accomplished  in  the 
body  only  in  the  liver.  Experimental  investigations,  both  in  physiology 
and  pathology,  have  made  it  most  probable  that  in  the  liver  it  has 
but  one  source  of  derivation,  the  cholesterol  of  the  red-blood  corpuscle. 
The  erythrocytes  have  a  limited  life  of  possibly  only  a  few  weeks' 
duration,  the  daily  depletion  of  the  circulating  blood  by  their  death 
being  made  good  by  a  corresponding  daily  regeneration,  the  forma- 
tion of  new  cells  in  the  red  bone  marrow.  The  disintegration  of  these 
erythrocytes,  in  its  final  stages  at  least,  occurs  in  the  liver;  and  from  the 


THE  BILE  173 

cholesterol,  which  is  a  prominent  constituent  of  the  stroma  of  these 
cells,  the  cholic  acid  is  formed.  Cholic  acid  we  may,  therefore,  term 
an  end  product  of  the  catabolism  of  erythrocytes,  the  expression  of  a 
special  metabolic  function  of  the  hepatic  cells.  If  the  liver  of  a  reptile 
be  extirpated,  no  cholic  acid  is  to  be  found  in  the  body,  where  normally 
it  occurs.  If  the  common  bile  duct  be  ligated  in  the  dog,  the  biliary 
acids  are  soon  found  in  the  blood ;  if,  however,  the  mouth  of  the  common 
thoracic  duct  be  ligated  also,  no  biliary  acids  are  to  be  found  in  the 
blood.  Apparently,  therefore,  in  two  as  widely  separated  species  as 
the  frog  and  dog,  cholic  acid  is  not  formed  outside  the  liver,  and  the 
sum  total  of  the  available  data  justifies  the  conclusion  that  the  forma- 
tion of  cholic  acid  is  an  exclusive  function  of  the  liver  and  that  probably 
the  chemical  source  of  the  cholic  acid  lies  in  the  cholesterol  of  the  red 
corpuscles  undergoing  cytolysis  in  the  course  of  daily  cellular  metab- 
olism. It  is  not  to  be  inferred  from  this  that  the  conversion  of  choles- 
terol to  cholic  acid  is  a  total  reaction.  On  the  contrary  free  cholesterol 
is  present  in  the  bile  and  pathological  erythrolysis  increases  the  choles- 
terol content  of  the  bile. 

Of  the  constitution  of  the  two  amino-acids  whose  combinations 
with  cholic  acid  form  the  biliary  acids,  glycocoll,  and  taurin,  we  are 
much  better  informed.  The  glycocoll,  simple  amino-acetic  acid,  is 
derived  from  the  common  catabolism  of  protein,  all  the  common  pro- 
teins yielding  on  hydrolysis  varying  amounts  of  glycocoll.  It  is,  there- 
fore, present  in  the  liver  at  all  times.  Glycocoll  is  also  formed  in  the 
liver  in  the  catabolism  of  erythrocytes,  whose  protoplasmic  protein 
undergoes  hydrolysis  there. 

Taurin  is  a  thio-amino-acid,  derived  from  cystein  according  to  the 
following  equation: 


Cystein  plus  oxygen  =  cystenic  acid  minus  C02  =  taurin. 
CH2SH  CH2S02.OH  CH2S02OH 

CH.NH2         ->        CH.NH2  -*      CH2.NH2 

COOH  COOH  C02 


Like  glycocoll,  cystin  is  available  in  the  liver  from  two  sources: 
derived  from  the  general  catabolism  of  protein,  since  it  is  the  sole  or 
chief  thio-amino-acid  contained  in  protein,  and  from  the  special  catab- 
olism of  the  protein  of  the  protoplasm  of  the  red  corpuscles  that  is 
localized  in  the  liver.  A  very  pretty  hypothesis  may  be  stated  in  the 
proposition  that  the  end  catabolism  of  the  erythrocytes  is  localized 
in  the  liver  and  the  three  chief  end  products  (cholic  acid,  taurin,  and 
bilirubin,  as  will  be  described)  are  eliminated  in  the  bile.  This  hypoth- 
esis rests  upon  the  assumption  that  just  as  the  cholic  acid  is  derived 
from  the  cholesterol  of  the  erythrocytes,  so  the  taurin  is  derived  from 
the  cystin  of  the  protein  of  the  erythrocytes,  the  cystin  derived  from 
the  common  protein  being  eliminated  in  the  urine  in  more  or  less 


174  DIGESTION 

completely  oxidized  sulphur  compounds.  Indirect  evidence  supports  this 
hypothesis.  If  taurin  be  administered  by  the  mouth  it  will  be  recovered 
in  large  part  in  the  urine  in  three  states:  unchanged,  as  a  substituted 
thio-urea,  and  in  part  completely  oxidized  to  sulphuric  acid.  Feeding 
with  taurin  or  cystin  leads  to  no  increase  in  the  taurocholic  acid 
of  the  bile,  obviously  because  there  is  no  further  available  cholic  acid. 
When,  however,  taurin  and  sodium  cholate  are  fed  together,  an  incre- 
ment of  sodium  taurocholate  is  found  in  the  bile.  It  is,  therefore,  clear 
that  the  liver  can  conjugate  cholic  acid  and  taurin  brought  to  it  in  the 
portal  circulation,  as  well  as  when  formed  within  its  own  tissues.  Un- 
less, therefore,  as  a  matter  of  mere  chance,  it  should  happen  that  the 
taurin  derived  from  the  cystin  formed  in  the  liver  from  the  catabolism 
of  erythrocytes  were  enough  to  combine  fully  with  the  cholic  acid 
formed  there  from  the  cholesterol  of  the  erythrocytes,  it  might  be 
assumed  that  the  liver  would  draw  upon  the  cystin  formed  in  the  liver 
and  elsewhere  in  the  catabolism  of  common  protein  and  with  taurin 
derived  therefrom  combine  the  excess  of  cholic  acid.  Yet  the  fact 
remains  that  the  liver  does  not  so  utilize  the  cystin  from  the  catab- 
olism of  common  protein;  this  is  eliminated  more  or  less  oxidized  in 
the  urine,  while  the  larger  fraction  of  the  cholic  acid  (in  man)  is  elimi- 
nated as  glycocholate  in  the  bile.  Albumin  of  blood  serum  contains 
nearly  2  per  cent,  of  sulphur,  all  of  which  is  converted  into  cystin. 
Now  on  a  basis  of  a  protein  ration  of  100  grams  per  day  and  a  sulphur 
percentage  of  only  1  per  cent.,  it  is  clear  that  the  liver  would  have 
presented  to  it  during  the  day  for  conjugation  with  the  cholic  acid 
more  than  5  grams  of  cystin  from  which  taurin  could  be  formed. 
This  is  many  times  the  amount  of  cholic  acid  formed  in  the  day.  Yet 
the  liver  refuses  this  cystin  from  the  common  protein  catabolism,  and 
eliminates  the  larger  fraction  of  cholic  acid  combined  with  glycocoll. 
This  speaks  for  the  hypothesis  that  the  taurin  (and  the  glycocoll  with 
the  same  probability)  eliminated  in  the  biliary  acids  is  derived  in  the 
catabolism  of  erythrocytes  alone,  and  not  drawn  from  the  products 
of  the  common  catabolism  of  protein.  Thus  we  have  the  hypothesis 
of  an  isolated  metabolism  in  the  liver;  the  erythrocytes  autolyzed 
there  and  the  end  products  (cholic  acid,  glycocoll,  and  taurin)  elimi- 
nated in  the  bile  so  long  as  the  cholic  acid  suffices,  any  excess  of  taurin 
and  glycocoll  being  sent  into  the  circulation  to  join  there  the  amino- 
acids  formed  from  the  common  catabolism  of  protein. 

Normal  stools  contain  no  biliary  acids,  but  only  traces  of  taurin 
and  of  cholic  acid,  the  original  acids  having  been  split  by  bacterial 
action.      In  the  meconium  the  unaltered  biliary  acids  are  present. 

The  salts  of  the  bile  include  those  of  sodium,  potassium,  and  calcium; 
chlorids,  sulphates,  and  phosphates. 

The  color  of  the  bile  of  the  liver  ducts  is  a  yellow  or  yellowish  brown. 
The  bile  of  the  gall-bladder  may  be  tinged  with  green,  a  deep  green,  or 
almost  back. 


THE  BILE  175 

Bilirubin. — In  the  bile  of  the  liver  ducts  is  to  be  found  one  pigment, 
termed  bilirubin.  This  originates  from  hematin  (a  tetrapyrrol)  derived 
from  hemochromogen  which  is  formed  when  hemoglobin  is  split  into 
its  two  groups  components,  hemochromogen  and  globin.  It  is  not 
to  be  inferred  that  these  are  the. sole  stages  in  this  reaction;  we  know 
very  little  of  the  chemistry  of  these  bodies.  The  formation  of  bili- 
rubin from  hematin  is  probably  an  exclusive  function  of  the  liver  cells; 
the  formation  of  the  hematin  from  hemochromogen  on  the  contrary  can 
apparently  occur  in  any  tissue.  The  splitting  off  of  the  iron,  which  is 
the  chief  fact  in  the  formation  of  bilirubin  from  hematin,  devolves 
upon  the  liver  cells.  Under  pathological  conditions,  in  connection 
with  extravasations  of  blood,  iron-free  pigments  are  formed  that 
resemble  bilirubin.  Particular  examination  has,  however,  demon- 
strated that  these  pigments  are  not  identical  with  bilirubin;  and  bili- 
verdin  cannot  be  derived  from  them.  The  bile  of  the  gall-bladder  may 
contain  not  only  bilirubin  and  biliverdin  but  also  urobilin,  whose 
presence  is  most  reasonably  to  be  ascribed  to  bacterial  action  within 
the  gall-bladder. 

Recent  investigations  have  thrown  much  light  on  the  chemical 
nature  of  the  blood  pigment  and  its  derivatives.  The  iron-bearing 
component  of  hemoglobin  is  hematin.  Hematin  is  a  complex  of  four 
pyrrol  groups,  linked  together  with  iron. 

— C— C  C— C— 

\  / 

N  N 


-c— c      \/     c— c- 

Fe 

-c— c     /\     c— c- 


N  N 

/  \ 

— c— c  c— c— 

To  the  four  pyrrol  groups  are  attached  ethyl  and  methyl  groups;  and 
different  peripheral  linkages  have  the  result  that  the  four  are  not 
identical,  two  reacting  in  one  direction  and  the  other  two  in  another 
direction.  The  iron  is  combined  by  replacement  of  the  imid-hydrogens 
of  the  nitrogen  atoms.  The  iron  is  in  the  ferro  state,  and  the  binding 
with  oxygen  is  to  be  interpreted  either  as  operative  through  the  ferri 
state  or  by  the  formation  of  peroxids.  From  the  hematin  is  derived 
bilirubin;  apparently  there  is  cleavage  of  the  molecule  in  the  liver, 
hematoporphyrin  is  first  formed,  and  from  it  bilirubin.  One  molecule 
of  hematin  will  yield  two  molecules  of  hematoporphyrin;  and  one 
molecule  of  the  latter  will  yield  one  molecule  of  bilirubin,  which,  there- 
fore, contains  two  pyrrol  groups.  Hematoporphyrin  is  an  acid  normally 
present  in  the  liver,  and  may  be  regarded  as  a  condensation  of  two 
molecules  of  a  hemo-pyrrol-carboxylic  acid : 


176 


DIGESTION 


H 

C  =  C— CH3 

/  I 


C  =  C— CH2.CH2.COOH 


H 

C  =  C.CH3 


N— N 


HOOC.H2C.H2C.C  =  C 

I 
H 


C  =  C.CH2.CH2.COOH 

I 
H 


Bilirubin  is  an  isomer  of  hematoporplryrin.  Under  different  condi- 
tions of  disease  and  intoxication  (as  a  result  of  sulphonal,  for  example) 
the  conversion  of  hematoporphyrin  into  bilirubin  is  in  part  checked, 
and  hematoporphyrin  appears  in  the  urine.  Urobilin  is  a  reduction 
compound  of  bilirubin,  but  apparently  contains  four  pyrrol  groups, 
i.  e.,  in  the  reaction  of  reduction  a  polymerization  occurs.  All  condi- 
tions leading  to  erytbrolysis  result  in  the  formation  of  excessive  amounts 
of  bilirubin,  the  end  product  of  hemachromogen.  Strikingly  erythro- 
lytic  are  certain  venoms,  bacterial  poisons,  phosphorus  and  arsenic, 
and  poisons  such  as  toluylendiamin,  pyrogallic  acid,  chlorates,  chro- 
mates,  and  phenylhydrazin. 

Of  particular  interest  is  the  fact  that  the  chlorophyls  are  closely 
related  to  the  hematins,  being  pyrrol  compounds  in  which  manganese 
takes  the  place  of  iron.  It  is  to  be  expected  that  continued  investiga- 
tions into  the  constitution  of  these  bodies  will  yield  valuable  informa- 
tion to  physiologist  and  pathologist.  As  will  be  pointed  out  in  another 
connection,  our  present  knowledge  of  the  constitution  of  hematin  leads 
us  to  infer  that  it  may  be  a  source  of  tryptophan. 

In  the  gall-bladder,  bilirubin  may  be  converted  into  biliverdin  through 
oxidation.    In  general,  the  equation  runs: 

Ci6H18N203  +  O  =  C16H18N204 

There  are  several  oxidation  stages  of  bilirubin  known;  of  these  the 
chemistry  and  properties  are  very  unclear,  and  they  will  not  be  further 
discussed.  The  bile  of  the  gall-bladder  usually  contains  some  bili- 
verdin, but  this  is  not  invariable.  In  any  event,  it  is  present  in  but 
small  amount,  as  most  of  the  bile  pigment  enters  the  intestine  in  the 
state  of  bilirubin.  Within  the  intestine  it  is  exposed  to  the  action  of 
bacteria,  and  is  there  in  part  reduced  to  urobilinogen.  The  extent  of 
this  reduction  depends  upon  the  activity  of  the  intestinal  flora,  the 
duration  within  the  intestine  and  apparently  to  some  extent  upon  the 


THE  BILE  177 

state  of  digestion.  Feces  normally  contain  no  bilirubin;  they  contain 
some  urobilin;  and  they  may  contain  biliverdin,  though  oxidations 
are  unusual  in  the  intestine  where  reduction  reactions  predominate. 
The  freshly  passed  stool  contains  largely  urobilinogen,  which  on  expo- 
sure to  the  air  is  oxidized  to  urobilin. 

Urobilin. — The  urobilin  formed  by  reduction  of  the  bilirubin  is  in 
large  part  absorbed,  in  part  excreted  in  the  stools.  Reduction  of  the 
bilirubin  to  other  related  pigments  as  stercobilin,  hydrobilirubin,  has 
been  described;  but  until  something  definite  is  known  of  these  supposed 
substances,  we  will  class  them  all  as  isomers  and  homologues  of  uro- 
bilin. The  urobilin  absorbed  from  the  intestine  is  carried  to  the  kidneys 
and  eliminated  in  the  urine,  being  one  of  the  chief  normal  pigments. 
In  the  urine  the  urobilin  is  supposed  to  coexist  with  another  yellow 
pigment,  termed  urochrome;  whether  they  are  identical,  whether 
isomers  or  homologues,  we  do  not  know.  Important,  however,  is  the 
fact  that  all  the  urochrome  and  urobilin  of  the  urine  are  of  intestinal 
origin;  none  are  normally  formed  within  the  tissues.  How  much  of 
the  urobilin  formed  in  the  intestine  is  absorbed  and  how  much  eliminated 
is  not  known,  there  being  no  quantitative  method  available  for  its 
estimation.  The  more  bulky  the  diet  and  the  more  frequent  the  evacua- 
tion of  the  bowels,  the  more  bilirubin  and  urobilin  are  to  be  found  in 
the  stools.  Conversely,  constipation  is  apt  to  be  attended  with  highly 
colored  urine,  since  the  prolonged  stay  of  the  feces  in  the  colon  permits 
of  more  complete  absorption.    The  individual  variations  are  very  wide. 

Urobilin  is  formed  in  the  aseptic  autolysis  of  the  liver,  and  may  be 
present  in  the  bile  within  the  liver.  This  fact  may  make  it  incorrect 
to  attribute  the  urobilin  of  the  urine  solely  to  the  intestinal  reduction 
of  bilirubin.  Pathological  urobilinuria  might  be  of  hepatic  as  well  as 
of  intestinal  origin. 

The  Phosphorus  Compounds  of  the  Bile. — The  bile  of  herbivora  is 
poorer  in  phosphorus  than  that  of  the  carnivora.  The  percentages 
run  from  less  than  TV  up  to  1  per  cent.,  human  bile  standing  midway 
in  the  scale.  Fish  bile  is  almost  devoid  of  phosphorus;  the  content 
is  very  low  with  most  marine  animals;  that  of  the  polar  bear  is  very 
high.  Three  forms  of  organic  phosphorus  are  met  with  in  human  bile; 
one  the  sulphophosphatid  described  under  the  sulphur  compounds; 
one  a  lipoid  behaving  like  a  lecithin;  and  one  a  very  complex  phosphatid. 
In  view  of  the  darkness  surrounding  the  chemistry  of  the  complex 
lipoids,  all  this  is  to  be  regarded  as  provisional.  It  is  so  difficult  to 
separate  the  organic  sulphur  from  the  organic  phosphorus  compounds 
in  the  bile,  that  one  is  not  in  a  position  to  determine  whether  the  combi- 
nations are  of  the  nature  of  chemical  compounds  or  physical  adsorption 
compounds.  From  the  phosphorus  content  it  may  be  calculated  that 
dried  human  bile  contains  from  10  to  20  per  cent,  of  these  lipoids. 
Bile  contains  neutral  fats  and  fatty  acids.  Whether  the  fatty  acids 
are  derived  from  cleavage  of  the  neutral  fats,  from  cleavage  of  the 
phosphorized  lipoids,  or  exist  preformed  in  the  secretion  of  the  liver 
12 


178  DIGESTION 

cells,  cannot  be  determined.  In  the  bile  these  fatty  acids  exist,  of 
course,  in  the  form  of  the  soaps  of  sodium,  potassium,  and  calcium. 

Lipoids. — Under  the  term  lipoid  then  we  comprise  the  neutral  fats, 
the  fatty  acids,  the  complex  thio-  and  phosphorized  fats,  and  with 
these  may  be  grouped  cholesterol.  In  this  classification  we  make  no 
distinctions  between  the  lipoids  in  which  the  phosphoric  acid  is  loosely 
combined  as  glycerol  phosphoric  acid  and  those  in  which  the  phosphoric 
acid  is  firmly  bound  in  the  nucleus  of  the  lipoid.  These  lipoids  are 
all  constituents  of  tissues  in  general.  Whether  their  presence  in  the 
bile  represents  an  act  of  secretion  (regarding  them,  therefore,  as  lipoids 
of  hepatic  origin)  or  an  act  of  systematic  elimination  is  not  known. 
If  the  latter  view  be  favored,  then  the  liver  is  to  be  regarded  as  the 
gland  through  whose  elimination  the  end  lipoids  of  the  body  are  dis- 
charged. Protoplasm  contains  a  lipoid-protein  complex.  When  the 
cell  undergoes  autolysis,  the  end  products  of  the  hydrolysis  of  the 
protein  appear  in  the  urine;  and  under  the  terms  of  this  hypothesis, 
the  end  products  of  the  lipoids  appear  unoxidized  in  the  bile  in  the 
form  of  the  substances  stated.  If  they  are  held  to  originate  in  the 
liver,  their  source  may  reasonably  be  sought  in  part  in  the  red-blood 
cells  with  whose  catabolism  the  liver  is  so  closely  identified.  For  the 
cholesterol  especially,  a  local  origin  has  been  usually  predicated  on 
the  hypothesis  that  the  formation  of  gallstones  is  not  associated  with 
excesses  of  cholesterol  in  the  body,  and  must,  therefore,  have  been 
due  to  an  excessive  formation  of  the  substance  in  the  liver.  Now  it 
is  as  a  matter  of  fact  quite  certain  that  cholesterol  is  secreted  by  the 
mucous  membrane  of  the  ducts  and  gall-bladder.  When,  however, 
one  considers  how  slowly  gallstones  are  formed,  bears  in  mind  the 
weights  of  gallstones  and  the  amount  of  cholesterol  in  normal  bile,  it 
is  clear  that  the  formation  of  gallstones  may  be  adequately  explained 
as  due  to  abnormal  conditions  of  crystallization  and  precipitation, 
and  requires  no  assumption  of  any  increased  formation  of  cholesterol. 
The  causes  of  the  abnormal  crystallization  and  precipitation  are  now 
believed  to  lie  in  the  presence  of  nuclei  consisting  of  bacteria  or 
epithelial  cells,  which  favor  greatly  the  crystallization  of  the  cholesterol. 

Lastly,  the  bile  contains  traces  of  urea,  ammonia,  and  other  organic 
substances,  whose  presence  is  incidental.  Traces  of  iron  are  also  present. 
It  is  probable,  however,  that  the  larger  fraction  of  the  iron  split  from 
hematin  in  the  liver  in  the  reaction  of  the  formation  of  bilirubin  is 
eliminated  by  the  small  intestine  and  not  by  the  bile,  where  its  presence 
is  to  be  regarded  as  incidental. 

Our  knowledge  of  the  function  of  the  formation  of  the  bile  is  very 
incomplete,  and  the  variables  are  scarcely  known,  since  the  experi- 
mental difficulties  in  investigations  are  extreme.  It  is  incorrect  to 
study  the  secretion  by  means  of  a  fistulous  opening  from  the  gall- 
bladder; the  fistula  must  be  made  by  transplantation  of  the  opening 
of  the  common  bile  duct  in  the  duodenum.  It  is  also  questionable 
to  what  extent  the  results  of  experiments  with  biliary  fistula?  in  the 


THE  BILE  179 

dog  can  be  applied  to  man,  or  even  to  the  normal  dog,  since  to  some 
extent  fistula  bile  is  different  from  bladder  bile  or  liver-duct  bile. 
Following  the  ingestion  of  food,  the  flow  of  the  bile  is  increased;  in 
other  words,  the  secretion  of  bile,  like  that  of  the  pancreas,  is  related 
to  gastric  digestion.  Meat  produces  the  largest  secretion,  fats  the  next; 
carbohydrates  in  the  diet  have  little  influence  on  the  secretion  of  bile. 

Functions  of  the  Bile. — Leaving  now  the  constituents  of  the  bile,  and 
disregarding  all  questions  concerning  the  secretory  or  excretory  nature 
of  the  several  constituents,  what  are  the  functions  of  the  bile?  It  is 
not  a  digestive  juice  in  the  direct  sense,  since  it  contains  no  ferments 
that  accelerate  the  hydrolysis  of  carbohydrates,  fats,  or  proteins.  It 
is,  however,  an  important  accessory  to  intestinal  digestion.  Not  only 
does  it  influence  the  action  of  the  ferments  of  the  pancreas  and  intestine, 
it  promotes  conditions  of  solubility  and  emulsification. 

Two  general  functions  have  long  been  popularly  ascribed  to  the 
bile:  stimulation  of  peristalsis;  and  antiseptic  action.  It  is  difficult 
to  show  directly  that  the  bile  stimulates  intestinal  peristalsis.  The 
frequent  and  prolonged  observations  of  the  bowel  movements  of 
jaundiced  individuals  have  led  to  conflicting  conclusions.  Of  much 
importance  it  is  not..  The  long-assumed  antiseptic  or  bacterial  action 
of  bile  is  practically  nil.  There  is  no  evidence  that  it  normally  checks 
or  in  any  way  controls  the  activity  of  the  intestinal  flora.  Practically 
it  may  be  said  that  if  the  diet  of  a  person  with  obstruction  of  the  common 
bile  duct  be  so  arranged  as  to  leave  no  excess  of  undigested  food,  espe- 
cially of  fats,  to  act  as  culture  media  for  the  intestinal  bacteria,  no 
exaggeration  of  intestinal  bacterial  activity  is  to  be  observed.  Intestinal 
indigestion  and  excessive  bacterial  intestinal  fermentation  are  more 
easily  aroused  in  the  jaundiced  than  in  the  normal  individual;  but  this 
is  due  to  the  lack  of  the  bile  in  the  processes  of  digestion,  and  not  to 
the  lack  of  an  antiseptic  action  of  the  bile.  The  gall-bladder  is  known 
to  be  a  good  culture  tube,  and  may  harbor  a  culture  of  the  typhoid 
bacillus  for  years. 

The  bile  has  little  relation  to  the  digestion  of  carbohydrates  in  the 
intestine.  While  it  has  a  slight  power  in  the  activation  of  the  pancreatic 
amylase  and  maltase,  this  is  wholly  subordinate. 

The  influence  of  the  bile  on  the  digestion  of  protein  in  the  intestine 
is  slight  though  positive.  The  important  activators  for  the  proteolytic 
ferments  do  not  lie  in  the  bile.  Nevertheless  the  presence  of  bile  results 
in  acceleration  of  tryptic  digestion.  Its  action  in  checking  digestion 
by  pepsin  when  the  gastric  contents  are  passed  into  the  duodenum, 
has  been  greatly  exaggerated.  If  the  bile  be  mixed  with  a  peptic  diges- 
tion mass,  a  precipitate  is  formed  that  includes  the  pepsin.  But  in 
all  the  experimental  work  on  digestion  with  fistulse,  no  such  precipita- 
tion has  ever  been  observed  in  the  duodenum  when  the  gastric  contents 
encountered  the  biliary,  pancreatic,  and  intestinal  secretions.  The 
alkaline  reaction  of  the  duodenum  and  the  action  of  the  trypsin  (which 


180  DIGESTION 

digests  pepsin  with  avidity)  suffice  to  check  peptic  digestion  in  the 
duodenum. 

Important  are  the  actions  of  the  bile  on  the  digestion  and  resorption 
of  the  fats.  These  actions  are  several.  Bile  activates  the  pancreatic 
and  intestinal  lipases.  The  bile  contains  also  a  zymo-excitor  for  the 
pancreatic  lipase.  This  property  lies  for  the  most  part  in  the  biliary 
acids;  some  activity  is,  however,  displayed  by  the  lipoids  of  the  bile. 
The  bile  aids  greatly  in  the  solution  of  the  neutral  fats,  fatty  acids 
and  soaps,  especially  of  triolein,  which  then  in  turn  acts  as  solvent 
for  the  fats  of  higher  melting  points.  In  a  large  measure,  the  action  of 
the  bile  on  the  solution  of  fat  is  dependent  on  the  presence  of  triolein 
or  oleic  acid.  If  a  pure  tristearin  be  ingested,  it  is  very  incompletely 
resorbed.  This  result  is  commonly  ascribed  to  the  high  melting  point 
of  the  tristearin.  This  is,  of  course,  important;  but  especially  favor- 
able is  the  solvent  action  of  the  triolein.  This  increase  in  solubility 
has  the  certain  result  of  enlarging  the  field  of  action  of  the  lipases. 
It  has  also  the  result  of  increasing  enormously  the  velocity  of  the 
resorption  of  the  fatty  acids,  a  feature  too  often  overlooked.  Finally, 
the  bile  aids  in  the  emulsification  of  the  intestinal  contents,  whereby 
the  velocity  of  the  cleavage  of  fats  into  fatty  acids  and  glycerol  is 
augmented.  These  influences  of  the  bile  on  the  digestion  of  fats  are 
demonstrable  in  test-tube  experiments  as  well  as  in  the  living  intestine. 
From  this  description  of  the  data,  it  is  clear  that  the  function  of  the 
bile  in  digestion  is  much  more  important  in  the  carnivora,  who  con- 
sume much  fat  preformed,  than  in  the  herbivora  who  consume  little 
fat.  In  fact,  in  the  ruminantia  the  bile  is  to  be  regarded  practically 
as  an  excretion. 

Pathological  Variations. — An  excess  of  the  secretion  of  bile  is  unknown; 
a  deficiency  in  the  secretion  is  hypothetical.  In  diarrhea  biliary  acids 
appear  unsplit  in  the  feces.  Unaltered  bilirubin  is  also  present  in  the 
feces  in  diarrhea.  The  absence  of  bile  from  the  digestive  tract  is  a 
frequent  pathological  condition,  the  result  of  obstruction  of  the  common 
bile  duct.  Of  this  condition  there  are  two  distinct  aspects:  the  state 
of  intestinal  digestion  in  the  absence  of  bile;  and  the  resorption  of 
the  bile  into  the  general  circulation,  followed  by  deposition  in  the 
different  tissues  of  the  body.  Jaundice,  with  its  manifestations,  is  to 
be  considered  as  a  true  auto-intoxication.  We  will  consider  here  only 
the  conditions  of  intestinal  digestion  in  the  absence  of  bile.  In  practice 
one  sees  this,  of  course,  in  connection  with  jaundice  from  obstruction. 
But  the  conditions  are  to  be  studied  more  clearly  and  with  fewer  compli- 
cations in  instances  of  biliary  fistulse,  in  which  the  bile  is  discharged 
outside  the  body  instead  of  into  the  duodenum,  the  body  tissues, 
however,  being  free  of  bile. 

After  what  has  been  said  of  the  influence  of  the  bile  on  the  digestion 
of  carbohydrate  and  protein,  little  disturbance  in  these  functions 
would  be  expected,  and,  as  a  rule,  none  is  to  be  noted.  On  the  contrary, 
positive  disturbances  in  the  digestion  of  fat  would  be  expected.    Such, 


THE  MASS  RELATION  OF  THE  DIET  181 

however,  are  often  not  to  be  observed.  Whether  disturbances  in  the 
digestion  or  absorption  of  fats  occur  seems  to  depend  in  large  part 
upon  the  diet  of  the  subject.  A  well-selected  diet,  relatively  poor  in 
fat,  is  usually  digested  in  a  normally  efficient  manner.  When  first 
seen,  the  subject  may  complain  of  symptoms  of  indigestion,  that  dis- 
appear when  the  diet  is  corrected.  Three  abnormalities  may  occur: 
the  undigested  residue  of  neutral  fat  may  be  excessive;  the  resorption 
of  the  fatty  acids  may  be  reduced;  and  bacterial  fermentation  in  the 
intestine  may  be  abnormally  active.  If  the  fat  in  the  diet  be  reduced 
to  50  grams,  and  the  fuel  needs  of  the  body  supplied  by  easily  digested 
carbohydrate,  the  digestion  of  fat  and  its  resorption  become  normal 
and  the  excessive  bacterial  fermentation  disappears.  In  some  instances 
large  amounts  of  fat  are  perfectly  digested  and  absorbed.  In  other 
words,  the  usual  load  of  the  fat  digestion  can  be  carried  by  the  intestinal 
and  pancreatic  juices,  but  an  overload  is  not  tolerated.  The  depriva- 
tion of  the  bile,  therefore,  reduced  the  range  of  adaptation  of  this 
function.  It  will  be  rarely  found  that  a  normal  minimal  ration  of  fat 
cannot  be  digested  without  the  bile.  With  increasing  amounts  of  fat 
in  the  diet,  the  defect  first  to  appear  is  faulty  resorption  (fatty  acids 
in  the  stools),  and  this  is  under  nearly  all  circumstances  in  these  cases, 
much  more  prominent  than  incomplete  cleavage.  Apparently  the 
activation  of  the  pancreatic  lipase  is  fully  accomplished  in  the  absence 
of  bile.  Reduction  in  the  solubility  of  the  fats  and  fatty  acids  and 
imperfection  in  emulsification  may  result  in  a  lowering  of  the  resorp- 
tion, and  may  indeed  lead  to  defective  cleavage  of  the  fats.  But,  as 
a  rule,  disturbances  appear  only  in  the  event  of  a  heavy  ration  of  fat 
in  the  diet,  and  they  are  then  more  likely  to  appear  with  the  use  of 
fat  of  high  melting  point  than  with  the  use  of  fat  of  low  melting  point. 
This  indicates  in  another  way  that  the  defect  concerns  the  function 
of  solution  and  resorption  rather  than  that  of  cleavage. 

•  When  all  is  said  and  done,  observation  of  cases  of  chronic  biliary 
fistula,  in  which  for  anatomical  or  pathological  reasons  it  is  impossible 
to  return  the  stream  of  bile  to  the  intestine,  has  taught  that  a  state  of 
ill-defined  poor  health  is  very  prone  to  develop.  It  is,  of  course,  possible 
that  this  may  be  due  to  the  absence  of  some  unknown  influence  of  the 
bile  within  the  intestine.  Most  of  these  cases,  however,  suffer  from 
septic  infection,  cirrhosis  or  degenerative  changes  of  the  liver,  or  from 
other  diseases;  and  to  these  the  states  of  ill-health  observed  are  more 
reasonably  to  be  ascribed.  Rarely  in  severe  organic  disease  of  the 
liver  the  bile  may  be  free  of  pigment,  the  biliary  acids,  however,  being 
present. 

THE   MASS   RELATION   OF   THE   DIET 

A  diet  contains,  apart  from  the  salts,  condiments  and  flavoring 
additions,  three  ingredients:  water,  the  digestible  solids,  and  the 
indigestible  solids.     The  indigestible  solids  are  of  little  importance 


182  DIGESTION 

to  the  chemical  functions  of  digestion,  but  are  of  importance  to  the 
motor  functions  of  digestion.  It  is  astounding  how  grossly  inaccurate 
is  the  average  personal  conception  of  the  masses  involved  in  mixed 
diets.  Only  one  who  has  participated  in  a  metabolic  experiment  really 
has  a  personal  sense  of  perspective  in  this  matter.  It  is  one  thing  to 
know  that  so  and  so  much  of  this  or  that  article  of  diet  has  such  and 
such  a  percentage  of  solids,  of  starch,  fat,  or  protein;  it  is  a  very  different 
matter  to  know  what  a  certain  unit  ot  food  means  on  the  table.  The 
most  striking  variables — from  person  to  person,  and  in  the  same 
individual  from  day  to  day  and  from  season  to  season — are  displayed 
in  the  unconscious  selection  of  the  masses  of  the  diet.  The  appetite  is 
commonly  supposed  to  record  in  some  way  the  needs  of  the  body.  In 
laboratories  where  long-continued  and  extensive  investigations  into 
the  digestion  and  nutrition  of  dogs  are  carried  out,  the  conviction 
prevails  that  to  a  goodly  extent  the  appetite  of  dogs  is  an  expression 
of  the  needs  of  their  nutrition.  A  dog,  not  under  daily  exercise,  will 
eat  less  of  a  stated  food  than  will  a  dog  under  daily  exercise,  even  if 
the  feedings  be  held  prior  to  the  time  of  exercise.  Dogs  refuse  on  warm 
days  what  will  be  eagerly  eaten  on  cold  days.  In  the  primitive  state, 
before  the  development  of  the  culinary  art,  this  may  have  held  true 
in  man.  Today  the  needs  of  the  body  in  diet  are  indeed  more  honored  in 
the  breach  than  in  the  observance.  By  this  it  must  not  be  understood 
that  the  desire  for  food  does  not  in  civilized  beings  present  indications 
of  the  needs  of  the  body.  But  we  have  been  so  modified  by  the  develop- 
ment of  culinary  art  and  gustatory  tastes  that  the  average  cultivated 
man  is  usually  quite  unable  correctly  to  interpret  the  meaning  of  his 
appetite.  The  average  individual  does  not  know  how  much  he  eats; 
he  does  not  know  whether  the  promptings  for  food  are  appetite  in  the 
animal  sense,  or  the  expression  of  a  highly  cultivated  esthetic  desire 
for  pleasant  sensations  of  the  gustatory  nerves.  One  of  the  most  strik- 
ing illustrations  of  this  fact  is  the  total  lack  of  relationship  between 
the  salt  needs  and  the  salt  tastes  of  civilized  people,  the  latter  exceeding 
the  former  many  fold.  The  range  of  the  individual  variations  in  diet, 
dependent  upon  age,  sex,  occupation  and  physical  type,  and  multiplied 
by  individualism  in  gustatory  taste  and  experiences,  is  still  further 
diversified  by  the  currency  of  numerous  theories  and  fads  of  diet.  A 
menticulture  founded  upon  the  ostensible  denial  of  the  existence  of 
matter,  and  co-existing  in  an  individual  with  a  personal  hypothesis 
of  nutrition,  constitutes  a  striking  illustration  of  the  combination  of 
lack  of  sense  of  humor  and  of  logic  developed  in  a  popularized  striving 
for  individualism. 

A  study  of  diets  of  all  kinds  indicates  that  within  the  widest  range 
of  choice  or  economic  compulsion,  the  values  fall  within  the  figures 
determined  by  scientific  experimentation.  Scattered  through  the 
literature  are  to  be  found  careful  studies  of  many  diets,  including  the 
following:  The  diet  of  the  lower  coolie  classes  in  Japan;  the  diet  of 
the  working  classes  of  India;  the  diet  of  the  negroes  of  our  southern 


THE  MASS  RELATION  OF  THE  DIET  183 

States  in  summer  and  in  winter;  the  diet  of  the  so-called  "poor  white 
trash"  in  our  southern  States;  the  diet  of  the  lower  classes  of  Italian 
peasants ;  the  diet  of  the  poorer  German  peasants ;  the  diet  of  the  inhabit- 
ants of  the  polar  regions ;  the  diet  of  tropical  tribes ;  the  diet  of  several 
barbaric  or  aboriginal  tribes;  the  diet  of  students  of  American  colleges; 
the  diet  of  the  so-called  upper  classes  in  Great  Britain  and  the  United 
States;  the  diet  of  vegetarians  and  fruitarians;  the  army  rations  of  all 
the  civilized  nations;  the  rations  in  civic  institutions  of  all  kinds, 
asylums,  prisons,  hospitals,  etc.  Under  these  widely  varying  circum- 
stances, the  amounts  of  protein,  fat,  and  carbohydrate  and  the  sources 
in  the  several  foodstuffs  of  the  protein,  fat,  and  carbohydrate  are 
variously  distributed.  And  yet  a  calculation  indicates  clearly  that 
under  all  these  circumstances  the  protein  input  is  always  as  high 
as  the  figure  determined  essential — a  gram  per  day  per  kilo  of  body 
weight — though  often  higher;  and  that  though  the  relations  of  fat  to 
carbohydrate  fluctuate  greatly,  the  caloric  needs  of  the  body  are  covered 
in  accordance  with  the  figures  of  our  closely  determined  standards. 
Man  is  truly  an  omnivorous  animal,  and  this  is  indeed  well  for  him. 
The  powers  of  adaptation  and  compensation  are  nowhere  better  illus- 
trated than  in  the  function  of  digestion  and  nutrition.  It  is  this  broad 
experimental  truth  that  places  the  ban  of  scientific  disapproval  upon 
every  exclusive  school  of  diet,  if  the  popular  fads  of  diet  may  be  so 
designated.  Of  course,  digestion  and  nutrition  can  be  maintained  with 
adherence  to  all  sorts  of  fad  diets — not  as  an  illustration  that  the  fad 
diet  is  correct,  but  simply  as  an  illustration  of  the  powers  of  adapta- 
tion— just  as  in  the  instances  of  the  different  dietaries  mentioned  above. 
The  term  "normal  diet"  must,  therefore,  be  given  a  very  wide  scope, 
and  for  further  information  we  must  depend  upon  carefully  planned 
and  executed  investigations  of  natural  classes  rather  than  upon  isolated 
laboratory  experiments. 

Masses  of  Normal  Diets. — Let  us  now  consider  the  masses  in  various 
normal  diets.  Included  in  the  mass  of  a  diet  is  the  input  of  water, 
whether  consumed  with  meals  or  between  meals.  Normally,  water  is 
consumed  with  meals.  Under  the  influence  of  a  recent  fad,  numbers 
of  individuals  now  take  no  fluid  witb  meals;  of  course,  they  get  along 
as  well,  and  no  better,  than  their  unfadded  fellowmen.  Since  the  water 
ingested  as  beverage  is  added  to  that  of  the  diet,  it  ought  to  be  originally 
included  in  the  calculations.  The  water  taken  daily  by  different  individ- 
uals varies  widely;  usually  it  will  run  from  half  a  liter  to  a  liter  and 
a  half;  it  may  fall  materially  below  a  half  liter,  and  may  be  as  high  as 
two  or  three  liters.  It  will  be  assumed  in  these  calculations  that  the 
water  taken  as  beverage  is  one  liter  per  day.  For  the  determination 
of  the  masses  of  the  diet,  the  protein  input  in  mixed  diets  will  be  fixed 
at  70  grams  per  day;  the  distribution  of  fats  and  carbohydrates  will 
express  largely  the  economic  basis  of  the  diet. 

A  milk  diet  for  an  adult  would  consist  of  5  liters  per  day,  if  the  input 
of  3000  Calories  is  to  be  attained.     Such  a  ration  is  not  only  rather 


184  DIGESTION 

large  in  bulk  (water  as  beverage  would  not  be  necessary),  but  it  is 
needlessly  heavy  in  protein,  150  grams  per  day.  If  to  3  liters  of  milk 
300  grams  of  sugar  were  added,  the  bulk  of  the  diet  would  be  more 
agreeable,  the  protein  input  reduced  to  nearer  the  requirements  and 
the  caloric  value  maintained.  This  could  also  be  attained  by  adding 
cream,  much  more  expensive  and  less  digestible  than  sugar.  The 
solids  of  a  milk  diet  of  5  liters  are  about  600  grams;  of  3  liters  plus 
300  grams  sugar,  660  grams.  The  total  sum  of  these  solids  is  digestible; 
it  will  not  be  all  resorbed,  but  it  is  all  digestible. 

A  pure  protein  diet  would  consist  of  750  grains  of  casein  per  day. 
Such  a  diet  can  be  borne  in  the  dog,  it  is  questionable  whether  a  man 
could  swallow  it  or  retain  it.  A  meat  diet  can,  however,  be  taken  by 
men  living  in  the  open,  and  especially  in  cold  weather,  without  diffi- 
culty, though  the  ration  becomes  tiresome.  If  fresh  meat  were  con- 
sumed and  choice  were  available,  it  would  be  best  to  have  the  ration 
consist  of  about  equal  parts  of  lean  meat  and  fat.  For  a  moderately 
active  life  such  a  ration  would  consist  of  about  1500  to  1800  grams  per 
day,  depending  upon  the  fatty  tissues  or  fat  utilized.  For  food  under 
circumstances  where  a  pure  meat  diet  is  necessary,  desiccated  meats 
are  now  available.  On  the  assumption  of  complete  desiccation,  such 
a  ration  would  consist  of  250  grams  each  of  protein  and  fat.  The  body 
could,  of  course,  handle  more  protein  and  less  fat,  or  more  fat  and  less 
protein — but  equal  parts  of  each  would  suit  the  average  digestion 
best.  Adding  the  water  to  the  weight  of  the  natural  meat  and  fat 
first  given,  the  total  mass  of  the  day's  ration  would  be  3000  grams. 
In  the  use  of  the  desiccated  meat,  one  liter  of  water  would  not  be  enough; 
a  man  would  need  to  drink  enough  water  to  bring  up  the  weight  to 
3000  grams.  All  the  solids  of  such  a  diet  would  be  classed  as  digestible; 
it  would  not  be  all  resorbed,  but  it  would  be  digested. 

Bread  represents  a  complete  diet.  Campers  who  have  tried  both 
bread  diet  and  meat  diet  are  a  unit  in  preferring  bread  diet  to  meat- 
fat  diet,  except  under  conditions  of  extreme  cold.  A  satisfying  ration 
of  bread  would  weigh,  with  a  liter  of  water,  2500  grams.  Camp  biscuit, 
which  differs  from  bread  in  an  added  content  of  fat,  is  rather  better, 
as  the  weight  can  be  reduced  to  1200  grams,  and  the  lesser  input  of 
starch  is  an  advantage.  The  solids  of  such  a  diet  would  be  about  900 
grams  for  both  bread  and  biscuit.  The  indigestible  residue  would 
be  less  than  40  grams  per  day. 

A  diet  of  buttermilk  and  potatoes,  commonly  used  in  the  treatment 
of  obesity,  would  weigh  5  kilos  (2  liters  buttermilk  and  3  kilos  cooked 
potatoes)  with  a  caloric  content  of  3000  Cal.  Since  few  could,  or  would, 
ingest  5  kilos  of  food  per  day,  the  rationale  of  the  use  of  this  regimen 
for  the  reduction  of  obesity  is  obvious;  an  ardount  of  the  diet  that 
satiates  physically,  does  not  contain  enough  heat  to  maintain  the  body 
temperature,  which  is  then  maintained  by  combustion  of  the  body  fat. 

The  usual  mixed  diet  of  civilized  communities  contains  from  75 
grams  to  150  grains  of  protein  ingested  as  meat,  eggs,  milk,  cheese, 


THE  MASS  RELATION  OP  THE  DIET  185 

bread,  cereals,  and  legumens,  the 'protein  of  meat  comprising  usually 
over  half  of  the  total  protein;  from  50  to  150  grams  of  fat,  consumed 
as  cream,  milk,  yolk  of  egg,  butter,  olive  oil,  fat  of  meat,  and  animal 
and  vegetable  fats  used  in  cooking;  and  from  300  to  600  grams  of 
carbohydrates,  in  the  form  of  cereals,  starches,  breads,  milk,  and  sugar. 
Tastes  favor  the  use  of  fats;  economy  is  against  them.  The  universal 
tendency  of  the  past,  to  vary  the  diet  with  the  season,  is  being  gradually 
eliminated  by  the  development  of  transportation  and  storage  facilities 
and  the  art  of  packing  fruits  and  vegetables,  these  all  operating  to 
increase  the  price  of  raw  produce  during  the  summer  and  to  reduce 
the  price  during  the  winter.  In  a  number  of  series  of  metabolic  investi- 
gations, the  writer  has  had  occasion  to  study  the  composition  of  the 
mixed  diets  of  free  choice  of  several  groups  of  adult  normal  men.  The 
weights  of  these  diets,  including  one  liter  of  water  as  a  beverage,  varied 
from  2500  to  3500  grams  per  day.  The  solids  of  these  mixed  diets 
varied  from  500  to  800  grams  per  day.  The  indigestible  solids  varied 
from  20  to  40  grams  per  day.  In  a  few  instances  the  diet  weighed  as 
low  as  2000  grams  per  day,  in  a  few  as  high  as  4000  per  day,  without 
in  any  instance  being  especially  individualistic.  These  figures  are 
fairly  representative  of  mixed  diets  of  adult  men  not  engaged  in  hard 
physical  work. 

Strictly  vegetarian  diets  must  naturally  present  large  bulk.  The 
more  intelligent  vegetarians,  who  consume  bread  and  the  cereals 
largely,  have  less  bulk  in  the  diet  than  have  those  who  incline  to  cover 
their  nitrogen  needs  with  legumens.  With  a  heavy  ration  of  dried 
beans  and  peas  in  the  diet,  the  total  bulk  can  be  held  lower,  but  such 
a  diet  is  apt  to  be  indigestible.  For  the  strict  vegetarian  more  than 
for  all  others,  bread  is  the  staff  of  life.  A  properly  selected  vegetarian 
diet  need  not  weigh,  with  the  liter  of  water,  over  3  kilos,  or  at  the  most 
4  kilos.  The  fruitarian  diet,  an  uncommon  and  recent  expression  of 
the  food  fad,  must  be  a  diet  of  still  greater  bulk,  unless  the  individual 
is  able  to  digest  regularly  large  amounts  of  nuts.  The  food  in  such  a 
diet  will  weigh  from  3  to  even  5  kilos  per  day.  The  solids  of  these  diets 
vary  from  500  to  900  grams  per  day,  since  for  the  most  part  starch  is 
the  main  fuel  and  fat  is  present  in  small  amount.  The  amount  of 
indigestible  solids  need  not  be  over  40  to  50  grams  per  day,  but  may  be 
as  much  as  100  grams.  Without  any  discussion  of  the  desirability  of 
such  large  indigestible  residues,  either  in  health  or  in  the  treatment 
of  constipation,  it  may  be  pointed  out  that  an  intelligent  use  of  fruits 
and  vegetables  will  enable  an  individual  to  secure  a  large  fecal  residue 
without  the  diet  being  either  indigestible  or  too  prone  to  bacterial 
decomposition.  What  is  wanted  is  indigestible  residue,  not  a  large 
residue  composed  of  material  in  itself  digestible  but  consumed  in  excess 
of  the  capacity  of  the  individual  digestive  system. 

The  diets  of  laboring  classes  furnish  striking  instances  of  adaptation. 
The  fish  and  rice  diet  of  the  Chinese  coolie  is  equivalent  to  the  potato 
and  herring  diet  of  the  North  German  peasant.     The  idea  that  the 


186  DIGESTION 

coolie  maintains  his  nutrition  upon  an  amount  of  food,  protein,  and 
starch,  that  would  not  be  found  sufficient  for  a  Caucasian,  is  erroneous. 
When  the  body  weight  of  the  coolie  is  taken  into  consideration,  the 
ration  is  within  modern  figures.  During  the  cane  season,  the  negro 
workers  in  the  fields  live  principally  upon  the  cane  juice;  and  the  saving 
power  of  sugar  for  protein  cannot  be  better  illustrated  than  in  the 
diets  of  these  laborers.  The  protein  input  during  this  brief  season  is 
low,  probably  not  over  40  grams  per  day;  but  the  great  excess  of  sugar 
makes  it  enough,  for  the  time  at  least. 

The  element  of  bulk  in  the  diet  is  one  too  frequently  left  out  of 
account.  Satiation  is  due  more  to  bulk  than  to  ingredients,  though 
certain  articles  of  food  notoriously  satiate.  It  is  possible  to  so  arrange 
a  diet  as  to  fill  the  stomach  thrice  daily  and  yet  not  maintain  nutrition. 
It  is  also  possible  to  maintain  nutrition  on  a  diet  whose  bulk  is  so  low 
that  it  does  not  furnish  over  one  good  meal.  The  tendency  to  fewer 
meals  is  based  upon  the  use  of  concentrated  foods  quite  as  much  as 
upon  the  idea  of  taking  less  food.  The  use  of  a  diet  of  large  bulk  has 
in  general  the  tendency  to  lower  the  percentage  of  resorption,  and  to 
increase  the  activity  of  bacterial  processes,  though  in  many  instances 
no  such  effects  are  to  be  noted.  The  now  popular  notion  that  the 
husks  and  shells  and  outer  coverings  of  foods  furnish  elements  indis- 
pensable to  good  nutrition  was  born  in  the  imagination  of  the  writer 
of  advertisements  of  patent  foods.  Whatever  the  relation  of  polished 
rice  to  beri-beri,  the  adoration  of  bran  is  worship  at  an  empty  shrine. 
On  the  other  hand,  there  is  no  doubt  that  the  use  of  a  too  concentrated 
diet,  devoid  of  indigestible  residue,  may  lead  to  impaction  of  feces, 
or  at  the  least  to  their  retention  in  the  body  for  prolonged  lengths  of 
time. 


RESORPTION    OF   THE   PRODUCTS    OF   DIGESTION 

There  is  no  resorption  of  the  products  of  digestion  by  the  mucous 
membrane  of  the  mouth  or  esophagus.  Only  sugar  could  be  concerned, 
since  the  proteins  and  fats  undergo  no  change  in  the  mouth.  The 
digestion  of  carbohydrates  in  the  mouth,  during  even  the  most  pro- 
longed mastication,  is  very  slight.  There  is  in  any  event  no  evidence 
that  the  mucous  membrane  of  the  mouth  and  esophagus  possess  the 
power  of  resorbing  sugar. 

Resorption  in  the  Stomach. — In  the  consideration  of  the  resorptive 
function  of  the  stomach,  it  is  necessary  to  realize  the  difference  between 
the  natural  conditions  in  digestion  and  the  forced  conditions  of  experi- 
mentation. The  question  of  the  resorption  of  the  products  of  digestion 
in  the  stomach  (except  in  the  case  of  the  administration  of  predigested 
foods),  concerns  sugars  alone,  since  the  fats  are  not  digested  in  the 
stomach  at  all,  and  the  digestion  of  the  proteins  does  not  reach  the 
stage  of  peptone.    It  may  be  positively  stated  that  no  undigested  fat 


RESORPTION  OF  THE  PRODUCTS  OF  DIGESTION  187 

and  no  protein  in  the  states  in  which  protein  is  found  in  gastric  diges- 
tion, are  there  resorbed.  With  the  carbohydrates,  there  is  some  degree 
of  digestion,  from  10  to  possibly  40  per  pent,  of  the  starches  may  be 
converted  into  sugar  in  the  stomach  before  the  acidity  of  the  gastric 
secretion  checks  the  action  of  the  salivary  ferments.  It  has  been  usually 
assumed  that  this  sugar  was  resorbed  from  the  stomach.  This  assump- 
tion is  probably  incorrect.  It  is  true  that  if  a  stomach  be  filled  with 
a  sugar  solution  and  the  pylorus  ligated,  sugar  will  be  resorbed.  It 
is,  on  the  other  hand,  very  probable  that  in  normal  digestion,  where 
water  is  being  continually  secreted  into  the  stomach,  and  the  contents 
gradually  passed  into  the  duodenum,  no  sugar  is  resorbed.  It  is,  of 
course,  difficult  to  prove  this.  Possibly  the  non-absorption  of  sugar 
in  the  stomach  may  be  due  to  the  layer  of  mucin-HCl  that  covers  the 
mucous  membrane,  through  which  salts  might  diffuse,  but  sugar  only 
with  difficulty.  In  the  intestine  mucin  is  much  less  in  evidence.  But 
if  the  sugar  be  resorbed  in  normal  digestion,  the  amount  resorbed  must 
be  small.  This  physiological  opinion  is  supported  by  pathological 
observations.  Instances  of  pyloric  obstruction  are  unfortunately 
frequent  enough.  Observation  of  the  processes  of  digestion  in  these 
cases  does  not  lead  to  the  view  that  there  is  any  material  resorption 
of  sugar  from  the  stomach.  Our  present  knowledge  may,  therefore, 
be  stated  as  follows:  experimentally,  the  resorption  of  sugar  from  the 
stomach  can  be  forced;  in  normal  digestion  it  does  not  occur  at  all, 
or  at  the  most  in  but  small  amount. 

It  is  also  clear  that  normally  no  water  is  resorbed  from  the  stomach. 
On  the  contrary,  the  stomach  is  an  active  secreter  of  water.  In  this 
regard,  the  stomach  in  the  carnivora  operates  conversely  to  the  psalte- 
rium  of  the  ruminants.  The  stomach  in  the  horse,  and  in  the  other 
non-ruminating  herbivora,  secretes  large  amounts  of  water.  In  the 
psalterium,  water  is  resorbed,  so  that  the  contents  when  passed  into 
the  lab-stomach  resemble  little  cakes  from  which  the  water  has  been 
pressed.  Normally,  the  human  stomach  does  not  secrete  water  as  freely 
in  the  event  of  copious  ingestion  of  water  with  the  meals  as  with  the 
ingestion  of  food  without  water.  For  the  pathologically  dilated  stomach, 
with  or  without  pyloric  obstruction,  it  is  known  that  the  water  secre- 
tion of  the  stomach  may  continue  in  spite  of  the  presence  of  large  accu- 
mulations of  water  there  and  to  the  great  detriment  of  the  patient. 

Resorption  from  the  Small  Intestine. — It  will  be  of  advantage  to  sub- 
divide this  subject  into  three  parts:  The  qualitative  resorption  of 
the  products  of  digestion;  the  quantitative  relations  of  the  same,  and 
the  action  of  the  resorption  membrane  upon  the  products  of  digestion 
during  their  passage  through  the  mucosa. 

The  resorption  of  the  products  of  digestion  occurs  through  the  lining 
epithelial  cells,  not  between  them;  it  is  intracellular,  not  intercellular. 
The  resorptive  function  of  this  lining  epithelium  is  not  to  be  defined 
in  terms  of  a  simple  transfusion  membrane;  nor  is  it  to  be  fully  defined 
in   terms   of   a  semipermeable   membrane.       Direct   experiment   will 


188  DIGESTION 

illustrate  this.  If  a  living  detached  intestinal  lining,  or  a  detached 
peritoneal  membrane,  be  studied  for  its  resorptive  properties,  such 
and  such  results  will  be  noted.  If  now  this  membrane  be  killed  with 
chloroform,  different  results  will  be  observed.  If  finally  the  membrane 
be  killed  with  formaldehyd,  still  different  results  will  be  obtained. 
The  differences  obtained  under  the  three  sets  of  conditions  may  be 
interpreted  as  follows:  The  fullest  properties  are  to  be  observed  with 
the  unaltered  detached  membrane.  Following  the  action  of  chloro- 
form some  of  the  reactions  disappear,  but  many  are  retained.  Follow- 
ing the  action  of  formaldehyd,  which  alters  greatly  the  state  of  the 
tissue,  all  the  distinctive  reactions  disappear,  the  membrane  retains 
only  the  properties  of  a  parchment  membrane.  After  the  action  of 
the  chloroform,  the  membrane  has  the  quality  of  semipermeability, 
but  has  lost  the  selective  properties  of  the  native  membrane.  These 
selective  properties  are  vested  in  the  chemical  and  physico-chemical 
attributes  of  the  living  cells.  Chloroform  kills  the  cells,  but  does  not 
alter  their  physico-chemical  properties  so  markedly  but  that  a  high 
degree  of  semipermeability  is  retained.  Formaldehyd  so  completely 
alters  the  chemical  and  physico-chemical  states  of  the  cells  as  to  destroy 
all  but  simple  transfusion,  such  as  is  displayed  by  a  parchment  mem- 
brane. The  explanation  of  the  selective  and  synthetic  properties  of 
the  living  epithelial  cells  is  not  to  be  sought  in  any  mystical  or  philo- 
sophical interpretation  of  the  term  "vital."  It  is  to  be  sought  in  a 
rational  understanding  of  the  chemical  and  physico-chemical  attributes 
of  living  cells,  attributes  as  yet  only  in  part  open  to  our  crude  methods 
of  investigation  and  analysis. 

An  histological  illustration  of  the  living  intestinal  membrane  will 
aid  the  visualization  of  the  concept  that  is  to  follow. 


Circulation 


Lumen  of  Intestine 


The  material  to  be  resorbed  must  first  pass  through  the  proximal 
lining  wall  of  the  epithelial  cells.  It  then  becomes  incorporated  with 
the  protoplasm  of  the  cells.  Later  it  must  pass  through  the  distal  lining 
wall  of  the  cells.  Upon  reaching  the  postcellular  space,  it  will  be  trans- 
ferred to  the  streams  of  circulation.  The  products  of  the  digestion 
of  carbohydrates  and  protein  pass  into  the  venous,  i.  e.,  portal  circula- 
tion; the  products  of  digestion  of  fat  pass  largely  into  the  lymphatic, 
i.  e.,  retroperitoneal  lymph  circulation.  We  do  not  know  what  deter- 
mines this  separation  of  the  routes  of  transportation.  For  the  present, 
the  question  does  not  concern  us.  Of  the  utmost  importance  here  is  the 
understanding  of  the  fact  that  during  the  act  of  passage  through  the 
cellular  membrane,  the  materials  are  for  a  time  incorporated  with 
the  protoplasm  of  the  cells.  And  within  the  very  limited  spacial  dimen- 
sions of  this  incorporation  are  encompassed  some  of  the  most  important 


RESORPTION  OF  THE  PRODUCTS  OF  DIGESTION  189 

synthetic  reactions  of  the  body.  The  lining  membrane  of  epithelium 
is  not  only  a  membrane  of  resorption,  it  is  also  a  tissue  of  synthesis. 
Possibly  it  would  be  correct  to  say  that  the  proximal  lining  wall  of  the 
cells — the  lining  facing  the  lumen  of  the  intestine — serves  as  the  direct 
transfusion  membrane;  the  synthetic  functions  devolve  upon  the 
protoplasm,  the  rear  lining  wall  being  permeable  to  the  synthesized 
products.  It  is  clear,  however,  that  under  such  an  interpretation  the 
rear  lining  wall  must  have  different  physical  properties  than  the  front 
lining  wall,  for  some  of  the  synthesized  products  are  colloidal,  and 
colloids  do  not  pass  through  the  anterior  lining  wall.  Let  us  now  apply 
this  conception  to  the  facts  for  the  resorption  of  the  different  food- 
stuffs, from  the  data  of  which  this  theory  was  originally  determined. 

Resorption  of  Carbohydrates.— The  facts  are  as  follows:  Maltose  can 
pass  through  the  intestinal  wall,  the  contents  containing  no  maltase. 
Cane  sugar  can  pass  through  the  intestinal  wall,  the  contents  contain- 
ing no  invertase.  Milk  sugar  can  pass  through  the  intestinal  wall, 
the  contents  containing  no  lactase.  Dextrose  passes  through  the 
intestinal  wall.  Dextrins  do  not  pass  through  the  intestinal  wall, 
in  the  absence  of  amylase  in  the  contents.  The  velocity  of  resorption 
of  monosaccharids  is  much  greater  than  of  disaccharids.  In  the 
blood  of  the  portal  system  after  all  these  experiments,  usually  only 
one  form  of  sugar  is  to  be  found,  namely,  d-glucose. 

The  explanations  must  be  as  follows :  Since  maltose  can  be  resorbed 
from  intestinal  contents  containing  no  maltase  and  reappears  in  the 
blood  on  the  other  side  in  the  form  of  d-glucose,  the  protoplasm  of 
the  lining  cells  must  contain  a  maltase,  and  a  reaction  of  cleavage  must 
occur  within  this  protoplasm.  Since  cane  sugar  can  be  resorbed  from 
intestinal  contents  containing  no  invertase  and  reappears  in  the  blood 
on  the  other  side  largely  in  the  form  of  d-glucose,  the  protoplasm  of  the 
lining  cells  must  contain  an  invertase,  and  a  reaction  of  cleavage  must 
occur  within  the  protoplasm.  Since  milk  sugar  can  be  resorbed  from 
intestinal  contents  containing  no  lactase  and  reappears  on  the  other 
side  in  the  form  of  d-glucose,  the  protoplasm  of  the  lining  cells  must  con- 
tain a  lactase,  and  a  reaction  of  cleavage  must  occur  within  the  proto- 
plasm. Since  dextrins  and  starches  are  not  resorbable,  the  protoplasm 
of  the  lining  cells  obviously  does  not  contain  amylase.  It  is  thus  very 
clear  that  within  the  protoplasm  of  the  lining  cells  important  digestive 
functions  are  vested — the  power  of  splitting  disaccharids  into  the 
component  monosaccharids.  So  far  as  we  can  judge,  the  body  could 
digest  these  disaccharids  in  the  entire  absence  of  maltase,  invertase, 
and  lactase  from  the  secretions  of  the  salivary  glands,  pancreas,  and 
succus  entericus.  It  might  be  natural  to  infer  that  the  resorbing  cells 
secrete  these  ferments  into  the  lumen  with  the  succus  entericus,  retain- 
ing some  ferment  within  their  protoplasm  to  act  upon  such  molecules 
of  disaccharid  as  might  escape  cleavage  within  the  lumen.  This  is 
doubtful.    Firstly,  because,  so  far  as  we  can  judge,  the  secretion  of  the 


190  DIGESTION 

ferments  of  the  succus  entericus  are  not  the  result  of  the  activity  of 
the  simple  lining  epithelium  (unquestionably  the  resorption  mem- 
brane), but  of  special  glands.  Secondly,  it  is  possible  directly  to  show 
that  the  lining  of  an  intestine  is  able  to  split  milk  sugar  when  the  succus 
entericus  is  unable  to  accomplish  this  reaction.  The  point  in  interpreta- 
tion is  not  important,  but  it  seems  most  likely  that  these  intracellular 
ferments  are  not  eliminated  into  the  lumen  of  the  intestine  with  the 
succus  entericus,  but  are  utilized  solely  for  intracellular  digestion. 
The  blood  and  the  other  tissues  do  not  possess  the  power  to  hydrolyse 
cane  sugar  and  milk  sugar.  It  is  upon  the  intracellular  lactase  and 
invertase  of  the  intestinal  epithelium  that  the  body  must  depend  for 
protection  from  the  presence  of  the  unaltered  disaccharids ;  whatever 
cane  sugar  and  milk  sugar  may  escape  intra-intestinal  cleavage  is 
subject  to  intracellular  cleavage  in  the  act  of  resorption  and  passage 
through  the  lining  epithelium.  It  might  even  be  suggested  that  this 
is,  in  the  adult,  the  sole  or  chief  method  of  digestion  of  milk  sugar, 
the  demonstration  of  lactase  in  the  pancreatic  and  intestinal  juices 
being  so  difficult  of  accomplishment. 

Since  one  of  the  component  primary  sugars  of  cane  sugar  and  milk 
sugar  respectively  are  d-levulose  and  d-galactose,  and  since  d-glucose 
only  is  to  be  found  in  the  blood,  it  is  clear  that  within  the  protoplasm 
of  the  lining  epithelial  cells,  or  liver,  d-levulose  and  d-galactose  are 
converted  into  d-glucose.  These  may  be  termed  acts  of  synthesis,  using 
the  term  in  its  ordinary  sense.  The  conversion  of  d-levulose  and 
d-galactose  into  d-glucose  means  the  conversion  of  one  stereoisomeric 
configuration  of  the  hexose  into  another.  It  can  be  accomplished  in 
the  laboratory  without  difficulty,  especially  in  the  case  of  drlevulose, 
which  on  standing  in  sterile  alkaline  solution  passes  into  d-glucose. 
As  an  hypothesis  of  physiological  chemistry,  d-glucose  may  be  regarded 
as  the  most  stable  stereoisomeric  state  of  the  hexoses,  toward  which 
the  d-levulose  and  d-galactose  naturally  tend.  These  conversions  do 
not  occur  within  the  lumen  of  the  alimentary  tract;  the  digestive  juices 
are  devoid  of  such  power.  The  great  importance  of  this  function  of 
the  intestinal  epithelium  is,  therefore,  apparent.  This  faculty  of  the 
protoplasm  of  the  lining  epithelium  rests  obviously  in  a  ferment,  a 
transformation  ferment  for  which  no  special  name  has  been  devised. 
It  may  be  here  recalled  that  d-galactose  occurs  not  only  in  the  milk 
of  the  active  mammary  gland,  but  also  in  the  central  nervous  system; 
since  only  d-glucose  is  to  be  found  in  the  blood,  it  is  clear  that  in  the 
breast  gland  and  in  the  central  nervous  system  this  reaction  can  be 
reversed  and  d-galactose  formed  from  d-glucose.  This  is  not  true  for 
d-levulose;  the  animal  body  does  not  normally  form  it  from  d-glucose, 
though  the  intestinal  epithelium  and  the  liver  can  form  d-glucose 
from  it. 

To  summarize,  the  following  reactions  of  digestion  occur  within 
the  protoplasm  of  the  lining  epithelium  of  the  intestinal  tract: 


RESORPTION  OF  THE  PRODUCTS  OF  DIGESTION  191 

Maltose  +  water  =  d-glucose  +  d-glucose. 
Cane  sugar  -f-  water  =  d-glucose  +  d-levulose. 
Milk  sugar  +  water  =  d-glucose  +  d-galactose. 

The  following  reactions  of  transformation  occur  there: 

D-levulose  —> d-glucose. 
D-galactose  — *  d-glucose. 

To  what  extent  the  hydrolytic  functions  of  these  cells  are  exercised 
in  normal  digestion  we  do  not  know.  Probably  by  far  the  larger  part 
of  the  cane  sugar  of  the  diet  is  split  in  the  intestinal  tract,  and  only  a 
small  part  resorbed  unsplit  is  hydrolyzed  within  the  protoplasm  of 
the  lining  epithelium.  For  milk  sugar  this  is  not  so  certain.  The 
demonstration  of  lactase  in  the  pancreatic  juice  fails  in  experiment; 
in  the  succus  entericus  it  is  difficult  of  demonstration,  and  when  present 
is  of  low  activity.  Yet  large  amounts  of  milk  sugar  are  easily  digested. 
We  may,  therefore,  fairly  ascribe  to  the  lactase  of  the  epithelial  proto- 
plasm an  important  range  of  function  in  the  digestion  of  milk  sugar. 

The  transformation  of  d-galactose  into  d-glucose  is  apparently  not 
confined  to  the  intestinal  epithelium.  The  conversion  of  levulose 
into  glucose  is  shared  with  the  liver.  And  if  a  goodly  amount  of  levulose 
be  ingested  on  the  empty  stomach,  its  resorption  occurs  so  rapidly 
that  much  reaches  the  liver  unchanged.  Normally  the  liver  converts 
this  levulose  into  glucose.  But  in  many  organic  diseases  of  the  liver 
this  power  is  reduced  or  lost,  the  levulose  passes  through  the  liver 
unchanged,  and  is  eliminated  in  the  urine. 

There  is  a  limit  to  the  action  of  the  invertase  and  lactase  of  the 
epithelial  protoplasm.  This  is  showed  in  the  fact  that  following  the 
ingestion  of  very  large  quantities  of  cane  sugar  or  milk  sugar,  most 
often  in  the  case  of  cane  sugar,  traces  of  saccharose  or  lactose  are  to 
be  found  in  the  urine.  This  means  simply  that  with  the  great  velocity 
in  resorption  from  large  amounts  of  concentrated  solutions  of  these 
sugars,  the  epithelium  is  so  to  speak  overwhelmed,  and  small  amounts 
pass  unhydrolyzed  into  the  retro-epithelial  spaces,  to  be  passed  into 
the  circulation,  thence  to  be  carried  through  the  liver  unchanged  to 
the  kidneys  for  elimination.  There  is  no  limit  to  the  reaction  of  trans- 
formation with  reasonable  amounts  ingested,  and  in  the  absence  of 
hepatic  disease,  i.  e.,  following  the  ingestion  of  even  large  amounts  of 
cane  sugar  or  milk  sugar,  d-levulose  or  d-galactose  is  not  to  be  found 
in  the  urine.  It  is  possible,  however,  that  proper  attention  has  not 
been  given  to  this  subject,  since  to  ordinary  examination  these  primary 
sugars  present  in  the  urine  would  pass  as  d-glucose. 

There  is  nowhere  in  the  digestive  tract,  either  in  the  juices  of  diges- 
tion or  in  the  resorption  membrane,  any  known  power  to  convert 
pentoses  into  hexoses.  There  is  evidence  that  pentoses  are  utilized 
in  the  body,  and  it  is  believed  that  their  utilization  follows  their  trans- 
formation into  d-glucose.    But  this  transformation,  so  far  as  we  know, 


192  DIGESTION 

does  not  occur  in  the  acts  of  digestion  or  resorption.  Direct  and  com- 
prehensive investigations  might  possibly  indicate  the  contrary;  there 
is  little  data  from  which  conclusions  may  be  drawn.  It  is  known  that 
within  the  body  pentoses  can  be  formed  from  d-glucose  and  conversely 
d-glucose  from  pentoses. 

The  Resorption  of  Protein. — Extensive  as  is  our  knowledge  of  the 
digestion  of  protein,  by  ferments  and  by  acids,  within  the  body  and 
without,  we  are  not  yet  fully  informed  as  to  the  facts  for  the  resorption 
of  the  products  of  protein  digestion.  It  is  not  a  question  of  how  far 
down  the  scale  of  the  products  of  protein  digestion  resorption  occurs; 
it  is  a  question  how  far  up  the  scale  it  may  occur.  The  data  are  con- 
flicting, but  it  is  clear  that  the  latest  data,  obtained  with  better  methods 
of  chemical  analysis  and  more  careful  experimentation,  indicate  that 
much  of  the  earlier  data  were  not  trustworthy.  The  amount  of  amino- 
acid  that  is  to  be  found  in  the  intestine  in  any  one  moment  is  no  evi- 
dence of  the  extent  of  cleavage,  since  the  amino-acids  are  absorbed 
very  rapidly.  With  increasing  knowledge,  the  tendency  is  more  and 
more  to  limit  resorption  to  products  low  in  the  scale.  Realizing  that 
possibly  this  tendency  may  be  put  somewhat  strongly,  it  is  probably 
a  fair  statement  that  a  judicious  interpretation  of  the  best  data  indicates 
that  the  resorption  of  the  products  of  the  digestion  of  protein  occurs 
in  the  states  of  polypeptid  and  below;  that  it  does  not  occur  with  or 
above  the  stage  of  peptone.  The  digestion  of  protein  may  not  proceed 
to  the  state  of  complete  cleavage  to  monamino-acids  and  di-amino- 
acids.  Bi-,  tri-,  tetrapeptids  and  polypeptids  may  be  included  in 
the  normal  end  products  of  the  natural  digestion  of  protein.  These, 
with  mono-  and  di-amino-acids  are  to  be  regarded  as  the  states  of 
resorption  of  the  products  of  the  digestion  of  protein.  This  conclusion 
is  based  partly  upon  the  results  of  experimental  work,  and  partly  upon 
induction.  Since  proteins  are  formed  of  amino-acids  as  building  stones, 
our  present  chemical  conceptions  of  their  composition  and  constitu- 
tion do  not  permit  us  to  believe  that  the  body  can  build  them  from  the 
peptones  of  another  animal  or  plant — the  reconstruction  must  be  more 
extensive  than  that.  Just  as  one  cannot  rebuild  a  house  by  merely 
taking  off  and  replacing  the  roof,  so  one  cannot  form  new  protein  in 
the  biological  sense  by  enlarging  a  foreign  peptone.  The  proteoses 
still  bear  the  biological  stamp;  we  cannot,  therefore,  conceive  them 
as  the  nuclei  for  the  formation  of  protein.  The  peptones  of  different 
proteins  are  very  different  bodies,  and  when  one  considers  that  serum 
albumin  and  serum  globulin  are  formed  from  what-not  mixtures  of 
protein  in  the  diet,  it  does  not  seem  possible  to  regard  peptones  as 
building  stones.  The  resistant  polypeptids  also  are  very  different 
bodies  in  different  peptones — contain  different  amino-acids.  Obviously, 
the  more  extreme  the  cleavage,  the  greater  the  freedom  of  choice  afforded 
the  synthetic  functions  in  the  building  of  protein.  This  induction  is 
supported  by  a  great  deal  of  experimental  and  chemical  investigation, 
and  we  are  thus  led  to  the  proposition  as  stated;  the  resorption  of 


RESORPTION  OF  THE  PRODUCTS  OF  DIGESTION  193 

the  products  of  the  digestion  of  protein  by  the  intestine  is  in  the  states 
of  peptids  and  di-  and  monamino-amino  acids.  These  and  these  alone 
are  able  to  afford  to  the  receiving  body  full  opportunity  for  the  bio- 
logical synthesis  of  protein.  This  conclusion  is  supported  further  by 
our  knowledge  of  the  phenomenon  of  anaphylaxis. 

In  another  place,  it  will  be  pointed  out  that  when  protein  is  burned, 
the  process  consists  first  of  hydrolytic  cleavage,  following  which  the 
amino-acids  are  deaminated.  The  oxy-fatty  acids  resulting  from  this 
process  may  be  burned  directly.  But  there  is  good  evidence  that  to 
some  extent,  probably  to  a  large  extent,  sugars  are  formed  from  them, 
to  be  added  to  the  general  sugar  content  of  the  body.  It  will  be  shown 
in  another  place,  that  the  body  resists  the  storage  of  protein;  that 
whenever  protein  is  ingested  in  excess  of  the  body  needs  it  is  promptly 
burned  and  the  nitrogenous  products  eliminated  in  the  urine.  Do 
these  processes  occur  within  the  alimentary  tract?  Are  the  amino- 
acids  subject  to  deaminization  within  the  intestine  or  in  the  intestinal 
wall,  and  the  fatty  acids  resorbed  as  such,  to  be  transformed  into  sugar 
in  the  liver?  The  data  today  are  decidedly  against  this  hypothesis. 
The  digestive  juices  of  the  alimentary  tract  contain  no  deaminization 
ferment.  The  bacteria  of  the  intestine  elaborate  deaminization  fer- 
ments that  operate  largely  in  the  colon  upon  the  amino-acids  that 
have  escaped  resorption.  There  is  no  evidence  that  they  operate  to 
any  material  extent  high  in  the  tract  where  the  end  products  of  the 
protein  digestion  are  resorbed.  Our  best  evidence  is  that  the  amino- 
acids  are  resorbed  as  such.  Their  cleavage  in  the  catabolism  of  protein 
is  not  a  function  of  the  digestive  tract,  but  of  the  tissues.  The  writer 
believes  that  all  protein  is  resorbed  in  the  state  of  peptids  and  amino- 
acids  and  recondensed  to  protein,  in  which  state  it  becomes  the  sub- 
strate of  the  protein  metabolism.  In  the  event  of  ingestion  of  amounts 
beyond  the  needs  of  the  body  for  repair  and  regeneration  of  the  cells, 
beyond  the  maintenance  of  the  status  quo  of  the  body  protoplasm, 
the  excess  of  protein  is  catabolized.  In  a  word,  the  digestive  tract 
is  not  concerned  in  the  catabolism  of  protein  at  all.  This  is  the  exclusive 
function  of  the  tissues. 

The  fact  that  the  blood  of  the  portal  vein  is  relatively  rich  in  ammonia 
has  been  urged  in  favor  of  the  deaminization  of  amino-acids  in  the 
intestine.  When  the  blood  proteins  are  formed  in  the  intestinal  wall, 
in  accordance  with  the  interpretation  here  adopted,  superfluous  amino- 
acids  will  be  left  over.  These  might  possibly  be  deaminated  in  situ,  and 
from  them  the  ammonia  of  the  portal  blood  derived.  Ammonia  is  also 
evolved  by  bacterial  action  within  the  intestine. 

It  having  been  made  very  probable  that  the  products  of  the  diges- 
tion of  protein,  whatever  the  type,  are  resorbed  in  the  form  of  peptids 
and  amino-acids,  once  these  have  passed  through  the  anterior  or  front 
wall  of  the  epithelial  cells  of  the  intestinal  mucosa  and  have  been 
incorporated  with  the  protoplasm  of  these  cells,  what  occurs?  The 
older  view  was  that  they  were  transported  in  this  state  to  the  liver, 
13 


194  DIGESTION 

there  to  be  converted  in  large  part  into  protein,  in  part  to  be  burned. 
It  was,  of  course,  recognized  that  these  end  products  might  pass  through 
the  liver  and  be  utilized  directly  in  other  tissues  of  the  body;  but  the 
larger  utilization  was  localized  in  the  liver.  For  this  view,  held  generally 
for  many  years,  there  was  no  direct  evidence;  it  simply  appeared  to 
be  the  natural  inference.  When  amino-acids  were  sought  for  in  the 
blood  of  the  portal  vein,  only  doubtful  traces  were  to  be  found.  This, 
however,  did  not  discredit  the  view,  since  if  one  were  to  calculate  the 
volume  of  portal  blood,  the  number  of  times  it  passes  through  the 
intestine  and  liver  in  the  time  consumed  in  a  digestion  and  divide 
this  figure  into  the  amount  of  amino-acids  furnished  by  the  digestion 
of  the  protein  of  a  meal,  it  is  clear  that  only  traces  of  amino-acids 
could  be  expected  to  be  present  in  a  particular  sample  of  portal  blood, 
representing  merely  a  momentary  phase  of  the  act  of  digestion.  The 
toxicity  of  the  portal  blood,  as  reported  in  dogs  and  geese  with  the 
Eck  fistula  and  its  apparent  dependence  upon  the  amount  of  protein 
in  the  diet,  was  also  taken  as  evidence  of  the  resorption  of  the  products 
of  protein  digestion  in  the  form  of  amino-acids.  It  is  not  now  possible, 
on  the  basis  of  the  analytical  evidence  at  hand,  to  consider  the  toxic 
symptoms  that  may  develop  in  connection  with  the  Eck  fistula  as  the 
results  of  amino-acids.  The  positive  chemical  demonstration  of  amino- 
acids  in  the  portal  blood  or  in  the  general  circulation  of  animals  with 
the  Eck  fistula  (or  in  the  normal)  has  never  been  accomplished.  As 
explained  above,  with  the  great  dilution  of  the  products  of  digestion  by 
the  enormous  volume  and  velocity  of  the  circulation,  such  could  hardly 
have  been  expected.  Within  recent  years,  moreover,  the  investiga- 
tions with  the  Eck  fistula  have  shown  that  the  results  of  this  operation, 
properly  performed,  have  been  greatly  exaggerated;  and  the  depend- 
ence of  the  symptoms  upon  the  amount  of  protein  in  the  diet  greatly 
overrated.  It  were  a  wise  man  who  could  state  today  in  what  manner 
the  Eck  fistula  modifies  the  protein  metabolism  of  the  animal  possessing 
it,  or  the  cause  of  the  symptoms  that  may  attend  it. 

The  more  prevalent  view  now  runs  to  the  effect  that  these  end  prod- 
ucts of  the  digestion  of  protein,  following  their  passage  through  the 
front  wall  of  the  epithelial  cells,  are  in  the  protoplasm  of  these  cells 
recombined  to  form  protein.  In  a  word,  the  cleavage  reaction  of  diges- 
tion is  reversed,  and  the  building  stones  are  again  united  to  form  pro- 
tein, which  is  then  passed  into  the  portal  circulation.  This  view  is 
not  capable,  at  present  at  least,  of  direct  demonstration.  It  is,  how- 
ever, strongly  supported  by  indirect  evidence  and  sound  fundamental 
considerations.  There  is  now  an  enormous  literature  on  the  biological 
specificity  of  the  proteins  of  the  body.  Under  all  conditions,  the  tissues 
of  the  body  form  higher  proteins  that  are  peculiar  to  itself.  To  accom- 
plish this,  as  has  been  pointed  out,  it  is  necessary  that  the  digestion 
of  protein  proceed  to  an  advanced  point  in  order  that  the  units  of  dis- 
integration, the  building  stones,  may  present  the  widest  variety  for 
selection.    There  is  strong  indirect  evidence  that  the  construction  of 


RESORPTION  OF  THE  PRODUCTS  OF  DIGESTION  195 

a  protein  by  the  body  is  preceded  by  the  almost  complete  tearing  down 
of  the  protein  material — either  in  digestion  or  in  tissue  metabolism. 
The  disintegration  of  a  protein  into  its  building  stones  and  the  recon- 
struction of  the  new  protein  from  these  building  stones  seems  to  be 
the  universal  method  of  the  protein  metabolism.  In  the  case  of  the 
digestion  of  sugars  and  of  fats,  direct  demonstration  can  be  accom- 
plished to  the  effect  that  the  states  in  which  these  substances  exist 
in  the  portal  and  lymphatic  circulations  are  the  states  in  Avhich  they 
are  to  operate  as  the  substrates  of  their  respective  metabolism.  There 
are  no  d-levulose  or  d-galactose  in  the  circulation,  only  d-glucose,  the 
regular  sugar  of  the  metabolism.  Now,  entirely  apart  from  the  question 
of  toxicity  of  the  products  of  the  tryptic  digestion  of  protein,  reasoning 
by  analogy  we  should  expect  to  have  the  end  products  of  the  digestion 
of  protein  recombined  in  the  intestinal  epithelium  to  form  protein. 
It  is  not  to  be  denied  that  the  tissue  cells  could  accomplish  this.  Evi- 
dently all  cells  and  especially  muscle  cells  have  some  anabolic  faculty 
for  protein.  Direct  experiments  with  the  liver,  however,  show  that 
when  amino-acids  are  passed  through  it,  these  are  deaminated  and  sugar 
formed  from  the  fatty  acid  fraction,  they  are  not  apparently  utilized 
for  the  formation  of  protein.  That  this  result  must  necessarily  speak 
against  the  formation  of  protein  from  amino-acids  in  the  liver,  is  not 
here  contended. 

Indirect  evidence  and  general  considerations  which  will  be  presented 
in  another  section  lead  us  then  to  the  view  that  the  synthesis  of  protein 
from  the  end  products  of  digestion  occurs  in  the  protoplasm  of  the 
epithelial  cells  of  the  intestine.  The  form  of  protein  may  be  safely 
stated  to  be  the  serum  albumin  and  serum  globulin  of  the  blood  serum. 
That  serum  albumin  should  be  regarded  as  the  primary  protein  in  the 
anabolic  series  and  the  globulins  placed  higher  in  the  scale  is  due  to 
the  greater  biological  specificity  of  the  globulins  as  contrasted  with 
serum  albumin.  For  us  at  this  time  we  rest  with  the  proposition  that 
serum  albumin  and  serum  globulin  are  formed  in  the  protoplasm  of 
the  epithelial  cells  of  the  intestines  from  the  end  products  of  the  diges- 
tion of  protein;  and  that  these  proteins  are  the  substrate  upon  which 
all  the  later  processes  of  metabolism  of  protein  in  the  body  are  based. 
Serum  albumin  and  serum  globulin  are,  in  a  word,  the  raw  materials 
of  the  protein  metabolism. 

It  will  be  recalled  that  all  the  common  forms  of  protein  are  composed 
of  the  same  amino-acids,  but  in  widely  different  proportions.  When 
now  the  protoplasm  of  the  intestinal  epithelial  cells  forms  serum  albumin 
from  them,  there  is  selection  and  some  of  the  amino-acids  will  not  be 
utilized,  they  are  superfluous.  What  becomes  of  these?  There  are 
two  possibilities.  Either  they  are  deaminated  in  the  intestinal  epithe- 
lium, and  the  ammonia  and  fatty  acids  carried  to  the  liver  to  be  con- 
verted there  into  urea  and  sugar;  or  they  are  carried  unchanged  to  the 
liver,  there  to  be  deaminated  and  converted  into  ammonia  and  sugar. 
The  latter  may  be  regarded  as  the  more  likely  occurrence.    In  either 


196  DIGESTION 

event,  this  could  account  for  the  amino-nitrogen  supposed  to  exist 
in  the  portal  blood. 

The  Resorption  of  Fats. — As  old  as  modern  physiology  is  the  question 
of  the  state  of  resorption  of  fat.  Decades  ago  the  question  was 
approached  by  histological  methods,  and  from  the  appearances  thus 
obtained  the  inference  was  drawn  that  fat  could  be  absorbed  unchanged, 
as  neutral  fat,  in  a  state  of  fine  globular  subdivision,  without  having 
been  acted  upon  by  the  juices  of  the  digestive  tract.  That  fat  was 
split  in  the  intestine  was  known  from  the  first;  the  question  was  whether 
all  the  fat  was  split,  or  whether  some  of  the  fat  might  not  be  resorbed 
in  the  unchanged  state.  It  has  now  become  clear  that  the  use  of  the 
histological  method  is  fraught  with  danger.  Within  recent  years,  how- 
ever, even  the  results  obtained  with  this  method  have  spoken  against 
the  idea  of  the  resorption  of  neutral  fats.  It  can  only  be  shown  that 
fat  is  present  within  the  cells;  it  cannot  indicate  whether  it  was  resorbed 
as  such  or  formed  within  the  cells.  If  the  problem  were  to  be  defined 
as  follows:  are  the  fats  absorbed  as  neutral  fats,  or  are  they  absorbed 
as  fatty  acids  and  glycerol  and  carried  as  such  into  the  circulation? 
the  demonstration  of  stained  neutral  fat  within  the  epithelial  cells 
would  bear  upon  the  question.  This  is  not  at  all  the  problem.  The 
neutral  fats  are  to  be  found  as  such  in  the  epithelial  cells.  The  ques- 
tion stands:  is  the  fat  absorbed  into  these  cells  as  such,  or  is  it  formed 
there  after  resorption  of  the  fatty  acids  and  glycerol  ?  Within  the  last 
ten  years  the  accumulated  evidence  points  more  and  more  strongly  in 
the  direction  of  the  statement  that  fats  are  resorbed  only  in  the  state 
of  cleavage.  In  other  words,  undigested  neutral  fat  is  not  capable 
of  resorption;  fatty  acids  and  glycerol,  the  products  of  hydrolysis  of 
fats,  are  alone  capable  of  resorption.  Resorption  of  fats,  as  of  protein 
and  starches,  must  be  preceded  by  digestion. 

The  hypothesis  of  the  resorption  of  neutral  fat  was  based  upon  the 
idea  that  if  it  were  in  a  state  of  extremely  fine  subdivision,  in  a  state 
of  minute  emulsion,  the  globules  could  be  carried  mechanically  through 
the  lining  of  the  intestine.  Whether  between  the  cells  or  into  the  cells 
and  by  what  forces  carried  through,  was  not  stated.  Modern  investi- 
gations in  physical  chemistry  have  taught  us  the  meaning  of  the  state 
of  emulsion  for  the  lipolytic  processes  of  the  intestinal  juices.  But 
there  are  no  data  to  indicate  that  the  state  of  emulsion  accelerates 
the  velocity  of  a  process  of  diffusion.  The  bile  and  the  alkaline  pan- 
creatic juice  bring  about  a  noteworthy  solution  of  the  fatty  acids.  And 
it  is  the  soluble  fraction  alone  that  is  available  for  diffusion.  That 
cells  can  take  up  particles  of  solids  has  been  shown,  best  for  plant 
cells.  But  there  is  no  direct  evidence  that  the  epithelial  cells  of  the 
intestine  take  up  the  solid  particles  of  neutral  fat.  All  the  indirect 
evidence  is  against  this  view. 

If  soaps  are  given  to  a  dog,  fat  will  be  formed  from  them.  Since 
there  is  no  evidence  of  a  synthesis  of  glycerol  within  the  lumen  of  the 
intestine,  the  conclusion  is  obvious  that  the  glycerol  is  synthesized 


RESORPTION  OF  THE  PRODUCTS  OF  DIGESTION  197 

in  the  protoplasm  of  the  epithelial  cells  and  there  joined  to  the  fatty- 
acid  of  the  ingested  soap  to  form  neutral  fat.  The  same  result  will  be 
obtained  if  free  fatty  acids  are  fed  to  a  dog.  If  fatty  acid  and  glycerol 
are  fed  to  a  dog,  microscopic  examination  of  the  intestinal  wall  will 
show  fat  in  the  protoplasm  of  the  epithelial  cells.  In  some  instances 
it  has  been  possible  to  effect  this  demonstration  with  excised  sections 
of  the  intestine. 

If  the  state  of  emulsion  alone  could  be  held  responsible  for  the  resorp- 
tion of  fat,  this  ought  not  to  be  limited  to  neutral  fats,  but  ought  to 
be  demonstrable  for  other  substances  that  can  be  gotten  into  a  state 
of  fine  emulsification.  The  experiments,  however,  indicate  the  con- 
trary. Many  colloids  can  be  brought  into  the  most  fine  subdivision, 
but  are  not  resorbable.  And  for  the  hydrocarbons  in  particular,  as 
paraffin,  it  can  be  shown  that  even  when  administered  in  the  most 
highly  emulsified  state,  where  the  particles  may  be  shown  to  be  smaller 
than  those  in  a  fat  emulsion,  no  resorption  occurs.  Any  fat  that  can 
be  split  can  be  resorbed;  nothing  is  resorbed  that  cannot  be  split. 

As  will  be  later  pointed  out,  the  resorption  membrane  does  not 
effect  any  qualitative  alteration  in  the  fatty  acids;  that  is,  oleic,  palmitic, 
and  stearic  acids  are  to  be  recovered  in  the  fat  of  the  lymphatic  duct 
in  the  same  proportions  they  held  in  the  fat  of  the  diet.  As  a  rule, 
also,  the  resorption  membrane  does  not  alter  the  alcoholic  component. 
Sometimes,  however,  this  can  be  done.  If  the  fat  of  the  walrus  (in 
which  the  glycerol  is  replaced  by  cetyl  alcohol)  be  given  to  a  human 
being,  as  was  once  done  in  the  case  of  a  fistula  of  the  thoracic  duct, 
the  fat  recovered  after  its  digestion  was  largely  in  the  state  of  tri- 
palmatin.  The  only  explanation  of  this  finding  lies  in  the  assumption 
of  cleavage  within  the  lumen  of  the  intestine,  resorption  of  the  products 
and  the  substitution  of  glycerol  for  cetyl  alcohol  in  the  recombination 
within  the  epithelial  cells  of  the  intestinal  lining. 

The  sum  total  of  the  data  of  today  justifies,  therefore,  the  belief 
that  fats  are  never  resorbed  undigested,  but  only  in  the  state  of  fatty 
acids  and  glycerol.  There  is  no  evidence  that  the  fatty  acids  are  ever 
synthesized  or  converted  into  each  other  in  the  intestinal  wall.  Glycerol 
can  be  formed  there  (or  obtained  from  the  circulating  blood  stream) 
and  abnormal  fats  can  thus  be  converted  into  normal  fats  or  glycerids. 
Some  abnormal  fats,  however,  are  split,  recombined  unchanged  and 
thus  added  to  the  fat  content  of  the  body. 

On  reaching  the  retroperitoneal  lymph  circulation,  ending  in  the 
thoracic  duct,  the  fat  is  held  largely  in  an  insoluble  state.  On  reaching 
the  blood,  for  a  time  this  persists;  before  long,  however,  the  blood 
presents  no  signs  of  lipemia.  This  is  due  in  part,  no  doubt,  to  the 
deposition  of  the  fat  in  the  different  tissues.  In  part,  it  is  due  to  the 
fact  that  the  blood  holds  a  certain  amount  of  fat  in  a  water-soluble, 
diffusible  state.  Whether  this  fat  is  in  combination  with  protein  or 
how  else  combined  is  not  known;  but  combined  it  is  in  a  state  soluble 
in  water   and   diffusible  through  a  common  parchment  membrane. 


198  DIGESTION 

It  is  tempting  to  assume  that  this  state  represents  the  active  state  of 
the  fat  for  the  reactions  of  metabolism;  and  that  neutral  fat,  wherever 
and  however  found,  is  only  storage  fat.  A  parallel  might  be  drawn 
from  the  carbohydrate  metabolism.  Glycogen  is  the  storage  state 
of  carbohydrate;  the  soluble,  diffusible  glucose  is  the  active  chemical 
state  for  the  purposes  of  metabolism,  i.  e.,  chemical  reaction. 

While  it  is  known  that  the  chief  resorption  of  fat  occurs  through  the 
lacteals,  still  resorption  into  the  portal  system  has  not  been  definitely 
excluded.  All  the  fat  ingested  at  a  feeding  has  never  been  recovered 
from  the  thoracic  duct,  but  this  experiment  is  not  to  be  given  an  exclu- 
sive interpretation.  That  fatty  infiltration  of  the  liver  follows  the 
ingestion  of  a  meal  rich  in  fat  proves  nothing  directly,  since  the  fat 
might  have  been  deposited  from  the  arterial  circulation.  In  the  cat, 
in  which  such  a  fatty  infiltration  of  the  liver  can  be  provoked  by  a 
heavy  feeding  with  cream,  fatty  infiltration  of  the  kidneys  is  still  more 
marked,  an  observation  that  robs  the  fact  of  the  occurrence  of  fatty 
infiltration  of  the  liver  of  any  special  significance. 

The  Synthetic  Functions  of  the  Intestinal  Epithelium. — These  may 
be  summarized  as  follows :  The  conversion  of  d-levulose  and  d-galactose 
into  d-glucose;  the  formation  of  serum  albumin  and  serum  globulin 
from  the  products  of  the  digestion  of  protein;  and  the  formation  of 
neutral  fats  from  glycerol  and  the  fatty  acids.  These  all  we  ascribe 
to  ferment  action.  The  formation  of  protein  and  fat  fall  under  the 
concept  "reversed  action"  of  ferment.  It  will  be  recalled  that  a  fer- 
ment simply  accelerates  the  velocity  of  a  reaction  in  whatever  direction 
it  may  be  proceeding.  Theoretically,  when  the  experimental  condi- 
tions can  be  obtained  each  ferment  or  catalyzer  will  accelerate  the 
velocity  of  its  reaction  in  either  direction — breaking  down  or  up- 
building. For  the  purposes  of  this  discussion  it  will  be  assumed  out- 
right that  these  reactions  of  synthesis  in  the  intestinal  wall  are  enzymic 
in  nature.  Whosoever  wishes  to  regard  them  as  vital  and  not  enzymic 
may  be  permitted  to  hold  that  opinion  without  discussion.  Under 
the  assumption  that  these  syntheses  are  enzymic,  two  interpretations 
are  possible.  One  is  that  the  syntheses  are  due  to  proteolytic  and 
lipolytic  ferments  identical  with  those  that  accomplish  the  cleavages 
within  the  lumen  of  the  tract.  The  second  is  that  special  synthetic 
ferments  are  concerned  therein.  It  is  again  the  question  of  dualism 
in  ferment  action.  Experiments  with  reversions  are  difficult;  the 
intricacies  are  to  a  large  extent  inherent  in  the  problem,  and  are  present, 
therefore,  in  experiments  with  inorganic  substances.  These  are  in- 
creased by  the  lability  of  organic  substances  involved  in  experimenta- 
tion with  the  biological  aspects  of  the  question.  Under  these  circum- 
stances, the  experimental  data  do  not  speak  decisively  for  either  point 
of  view.  But  the  weight  of  physico-chemical  theory  and  analogy  is 
decidedly  on  the  side  of  the  view  that  such  reversions  (especially  in  the 
case  of  fat),  are  due  to  the  action  of  the  same  ferments  that  produce 
the  cleavage  in  digestion.     In  the  case  of  the  proteins,  the  biological 


RESORPTION  OF  THE  PRODUCTS  OF  DIGESTION  199 

specificity  of  the  serum  albumin  and  serum  globulin  formed  from  the 
diversified  proteins  of  the  diet  pleads  against  the  interpretation  of 
synthesis  by  the  same  ferment  that  accelerates  hydrolysis. 

Time  Relations  of  Resorption. — There  is  no  direct  experimental  way 
of  measuring  the  rate  of  resorption  from  the  intestine.  Indirect  evi- 
dence, the  known  data  of  the  heat  curve  following  the  ingestion  of 
varying  amounts  of  protein,  and  the  curve  of  the  output  of  nitrogen, 
enable  us,  however,  to  make  an  approximate  computation.  The  resorp- 
tion is  very  rapid  early  in  the  course  of  intestinal  digestion.  Probably 
within  two  hours  after  the  stomach  has  begun  to  discharge  its  contents 
regularly  into  the  duodenum,  the  maximum  of  the  curve  of  resorption 
is  reached.  Within  four  or  at  least  six  hours  after  the  stomach  begins 
to  discharge  its  contents  into  the  duodenum,  the  resorption  is  practically 
completed.  In  fact,  it  might  be  said  that  intestinal  digestion  and 
resorption  are  completed  almost  as  soon  as  the  stomach  is  emptied 
of  its  contents.  Digestion  is  very  rapid  in  the  intestine,  most  rapid 
for  the  carbohydrates,  less  so  for  the  protein,  least  so  for  the  fats. 
Resorption  is  also  very  rapid,  and  the  order  remains  the  same;  sugar, 
protein,  and  fat. 

Space  Relations  of  Resorption. — The  most  active  resorption  occurs 
in  the  lower  duodenum  and  upper  jejunum.  The  curve  of  resorption 
plotted  for  the  whole  small  intestine  would  rise  sharply  to  the  begin- 
ning of  the  jejunum,  and  then  fall  away  gradually  to  the  lower  part 
of  the  ileum.  It  is,  however,  very  doubtful  if  this  expresses  in  any 
way  the  powers  of  resorption  of  the  different  sections  of  the  intestine. 
For  it  must  be  remembered  that  the  lower  duodenum  and  upper  jeju- 
num have  presented  for  their  action  the  most  concentrated  solutions 
of  products  to  be  resorbed,  the  greatest  absolute  amounts  of  the  end 
products  of  digestion.  If  a  cut-off  be  established  between  the  lower 
end  of  the  duodenum  and  the  upper  end  of  the  ileum,  so  that  the 
jejunum  is  excluded  from  resorption,  it  will  be  found  that  the  velocity 
of  resorption  is  in  nowise  lowered  thereby.  In  other  words,  the  upper 
ileum  absorbs  as  well  as  the  jejunum,  when  it  has  the  same  opportunity. 
This  would  not  hold  for  the  lower  ileum.  Practically  no  resorption 
occurs  from  the  colon. 

Relation  of  Velocity  of  Resorption  to  Mass  of  Content. — Other  things 
being  equal— digestibility  of  contents,  total  mass,  etc. — the  time  of 
resorption  is  not  materially  lengthened  by  moderate  increase  in  the 
amounts  to  be  resorbed.  Though  this  cannot  be  shown  directly,  it 
may  be  inferred  from  indirect  evidence.  When  the  resorption  is  studied 
in  a  localized  portion  of  the  intestine,  it  seems  that  with  a  constant 
volume,  the  velocity  of  resorption  is  proportional  to  the  concentra- 
tion of  the  substance  to  be  resorbed;  when  the  concentration  is  held 
constant,  the  velocity  of  resorption  is  proportional  to  the  volume 
placed  in  the  intestine.  From  this  we  are  permitted  to  infer  that  the 
prolongation  in  the  time  of  digestion  that  is  observed  after  gorging 
is  due  to  retardation  of  the  chemical  processes  of  digestion  more  than 


200  DIGESTION 

to  retardation  in  resorption.  This  may  not  be  strictly  true;  but  it  is 
quite  certain  that  within  wide  limits,  the  fats  being  least  resorbable, 
the  intestinal  wall  absorbs  the  products  of  digestion  about  as  fast 
as  they  are  furnished  by  the  chemical  processes  of  digestion. 

Relation  of  Bulk  in  the  Small  Intestine. — The  total  bulk  presented 
to  the  intestine  in  the  day  is  large.  Let  us  say  that  a  mixed  diet  con- 
tains with  the  water  taken  as  beverage,  3  kilos.  To  this  must  be  added 
a  kilo  of  saliva,  half  a  kilo  of  gastric  juice,  a  kilo  of  bile,  and  possibly 
half  a  kilo  of  pancreatic  and  intestinal  juice.  The  total  is  6  or  7  kilos. 
The  average  stool  from  such  a  diet  will  weigh  not  over  100  or  200  grams. 
Of  the  rest,  600  or  700  grams  of  solids  and  in  the  neighborhood  of 
6  liters  of  water  have  been  resorbed  in  the  intestine.  This  is  divided 
into  three  meals,  extending  over  a  time  of  some  sixteen  or  eighteen 
hours,  making  2  kilos  per  meal.  Now  the  earlier  idea  was  that  the 
stomach  delivered  its  contents  to  the  duodenum  in  rather  large  con- 
signments. This  we  know  not  to  be  true.  When  the  pylorus  relaxes, 
a  very  small  amount  is  passed  into  the  intestine.  When  the  acidity 
of  this  portion  of  contents  in  the  duodenum  is  neutralized,  the  pylorus 
again  relaxes  and  another  small  portion  is  admitted  into  the  duodenum. 
It  is  the  duodenum  that  holds  the  pyloric  string,  the  stomach  is  willing 
to  empty  en  bloc.  The  neutralization  of  the  gastric  acidity  is  not, 
however,  the  sole  method  of  regulation,  since  this  mechanism  is  followed 
even  in  the  absence  of  gastric  acidity. 

Now  it  is  not  to  be  inferred  that  as  the  successive  consignments 
from  the  stomach  are  neutralized  they  accumulate  in  the  intestine, 
so  that  we  would  within  a  few  hours  have  the  total  mass  within  the 
intestine  increased  in  proportion  to  the  amount  of  the  gastric  contents. 
By  no  means.  The  resorption  of  water  proceeds  so  rapidly  in  the 
upper  small  intestine  that  it  is  scarcely  an  exaggeration  to  say  that 
it  is  absorbed  as  fast  as  it  enters  from  the  stomach.  While  it  is  true 
that  desiccation  of  the  feces  occurs  in  the  colon,  a  stool  of  100  grams 
weight  in  an  individual  with  the  habit  of  daily  defecation  probably 
did  not  weigh  over  200  grams  when  it  entered  the  head  of  the  colon. 
The  upper  intestine  acts  in  the  resorption  of  water  as  actively  as  the 
psalterium  of  cattle.  So  that,  as  a  matter  of  fact,  the  bulk  of  the  con- 
tents of  the  small  intestine  is  not  greatly  increased  during  the  time 
of  intestinal  digestion.  With  2  liters  of  fluid  to  resorb  with  each 
meal,  it  is  doubtful  if  the  bulk  of  the  contents  of  the  small  intestine  is 
increased  over  half  a  liter  at  any  time.  From  four  to  twelve  hours 
are  required  for  the  passage  of  a  marked  content  from  the  duodenum  to 
the  colon. 

The  Modus  Operandi  of  Intestinal  Resorption. — This  is  a  difficult  sub- 
ject to  discuss.  On  the  one  hand  stand  the  failures  of  those  who  have 
attempted  to  force  an  interpretation  of  the  process  of  resorption  to 
fit  gross  physical  concepts.  On  the  other  hand  stand  the  vitalists, 
holding  that  no  physico-chemical  explanation  is  possible.  For  those 
of  us  who  believe  that  in  the  ultimate  all  manifestations  of  life  rest 


RESORPTION  OF  THE  PRODUCTS  OF  DIGESTION  201 

upon  chemical  and  physical  properties,  the  position  of  the  vitalist  is 
as  irrational  as  the  traditional  practice  of  the  ostrich.  On  the  other 
hand,  our  knowledge  of  chemistry  and  physics  and  our  ability  to 
reproduce  essential  conditions  in  experimentation  directed  to  the 
elucidation  of  such  a  complex  problem  as  resorption,  are  limited;  and 
we  must  expect  to  fail  today  where  we  may  succeed  tomorrow.  If 
the  present  physical  theories  cannot  be  conclusively  applied  to  the 
data,  under  the  present  conditions  of  experimentation,  this  furnishes 
no  basis  for  an  ultimate  conclusion.  A  number  of  physical  and  physico- 
chemical  factors  can  be  shown  by  direct  experiment  to  play  a  role  in 
resorption  from  the  intestine.  No  one  of  these  factors  can  be  held  to 
satisfactorily  explain  all  the  known  facts.  Nor  is  it  now  possible  to 
combine  these  several  factors,  in  an  experimental  way,  so  as  to  repro- 
duce the  phenomena.  It  must  be  realized  at  the  outset  that  the 
problems  of  the  resorption  of  the  products  of  digestion  and  of  metallic 
salts  are  not  identical.  There  is  evidence  that  the  resorption  of  the 
products  of  digestion  is  entirely  intracellular.  On  the  other  hand, 
there  is  good  evidence  that  the  resorption  of  the  metallic  salts  is  largely 
if  not  entirely  intercellular.  Thus  the  results  of  experiments  on  the 
reactions  of  the  intestine,  within  the  body  and  without,  to  different 
solutions  of  metallic  salts  cannot  be  directly  applied  to  the  problem 
of  the  reaction  of  the  intestine  to  the  products  of  digestion. 

It  will  suffice  for  our  purpose  to  name  and  define  the  several  factors 
that  are  of  known  influence  in  the  resorption  of  the  products  of  diges- 
tion from  the  intestine. 

Diffusion;  Osmotic  Pressure. — This  is  a  factor  of  great  importance 
in  the  resorption  of  salts,  but  of  lesser  importance  in  the  resorption 
of  the  products  of  digestion.  The  osmotic  pressure  of  sugar  is  high,  of 
amino-acids  low,  of  fatty  acids  very  small.  The  resorption  of  sugar  is 
moref  rapid|than  that  of  amino-acids,  and  much  more  rapid  than  that 
of  the  fatty  acids ;  but  the  velocities  of  these  resorptions  are  not  related 
to  each  other  as  are  the  osmotic  pressures  of  the  solutions  of  these 
substances.  For  metallic  salts  the  rates  of  resorption  run  parallel  to 
the  diffusion  velocities,  the  latter  being  the  expression  of  the  coeffi- 
cients of  dissociation  of  the  molecule  and  the  migration  velocity  of 
the  ions.  This  has  clearly  no  determining  application  to  the  resorp- 
tion of  sugar,  amino-acids,  and  fatty  acids.  Sugar  is  resorbed  more 
rapidly  than  proportional  to  its  diffusion  velocity;  for  the  amino-acids 
no  data  are  available;  the  fatty  acids  are  resorbed  far  more  rapidly 
than  in  proportion  to  the  diffusion  velocity.  The  same  fact  holds  true 
for  urea  and  for  many  other  organic  substances.  The  factor  of  osmotic 
pressure  per  se  could,  under  the  theory  of  resorption  of  the  products 
of  digestion  through  the  protoplasm  of  the  epithelial  cells  of  the  intes- 
tinal lining,  apply  at  the  most  only  to  the  passage  of  the  substances 
through  the  anterior  cell  wall.  The  known  facts  for  the  relationship 
of  resorption  to  osmotic  pressure  hold,  with  quantitative  differences, 


202  DIGESTION 

for  the  dead  intestinal  wall;  and  hold  also  to  some  extent  for  artificial 
gelatinous  membranes. 

Molecular  Imbibition  and  Capillary  Imbibition. — These  have  been 
invoked  in  explanation  of  the  resorption  of  the  products  of  digestion. 
Their  importance  at  the  most  must  be  small,  since  the  capacity  for 
imbibition  of  a  tissue  like  the  intestine  is  low.  For  the  intercellular 
resorption  of  salts,  imbibition  may  have  an  importance;  for  the  intra- 
cellular resorption  of  the  products  of  digestion,  it  can  have  none  of 
moment. 

Intra-intestinal  Pressure. — Of  great  importance,  as  illustrated  in 
direct  experiments  with  the  living  intestine,  is  the  intra-intestinal 
pressure.  In  this  intra-intestinal  pressure  are  several  factors:  the 
tone  of  the  intestinal  wall;  the  weight  of  the  intestinal  tract;  the  con- 
tracture of  the  intestinal  muscularis;  the  pressure  of  the  abdominal 
wall;  and  the  pressure  of  the  diaphragm.  During  inspiration  the 
diaphragm  exerts  pressure;  during  expiration  the  abdominal  wall 
exerts  pressure.  By  opening  the  abdominal  wall,  by  removing  the 
pressure  of  the  diaphragm,  by  placing  within  the  peritoneal  cavity 
varying  compressions  through  the  presence  of  fluids,  by  releasing  the 
gases  from  within  the  intestine  and  by  obliterating  peristalsis,  it  is 
possible  in  direct  experiment  to  create  many  different  modifications 
in  the  intra-intestinal  pressure  and  to  study  the  conditions  of  resorp- 
tion under  these  varying  circumstances.  Such  tests  have  demonstrated 
the  great  influence  of  variations  in  intra-intestinal  pressure  upon  the 
velocity  of  resorption.  This  pressure  does  not,  of  course,  create  more 
than  a  physical  tendency  to  the  passage  of  a  substance  through  the 
intestinal  wall;  it  simply  aids  the  passage  by  direct  pressure  from 
behind,  just  as  increased  atmospheric  pressure  will  accelerate  the 
filtration  of  a  solution  through  a  filter.  It  is  a  quantitative  force 
merely,  but  undeniably  one  of  great  importance. 

Blood  Pressure. — The  blood  pressure  in  the  arterial  capillaries  aids 
in  resorption  by  driving  the  resorbed  fluids  into  the  capillaries  leading 
to  the  portal  system.  The  lower  the  concentrations  of  resorption 
material  behind  the  separating  membrane,  the  greater  the  velocity 
of  the  purely  physical  stream  of  diffusion.  This  is  a  factor  usually 
neglected  in  experiments. 

Surface  Tension  and  Semipermeability. — Two  further  physical 
factors,  of  undoubted  importance,  but  as  yet  outside  of  experimental 
measurement,  are  the  surface  tension  of  the  emulsified  intestinal  con- 
tents and  the  semipermeability  of  the  intestinal  wall.  That  the  mem- 
brane of  lining  epithelium  is  semipermeable,  in  the  same  sense  as 
artificial  semipermeable  membranes  though  with  different  qualitative 
manifestations,  is  well  known.  These  two  factors  must  certainly  influ- 
ence the  processes  of  resorption  in  both  qualitative  and  quantitative 
directions. 

Physico-chemical  Constitution. — Are  we  warranted  in  the  assumption 
that  the  resorption  of  the  products  of  the  digestion  of  carbohydrates, 


RESORPTION  OF  THE  PRODUCTS  OF  DIGESTION  203 

proteins,  and  fats  are  accomplished  solely  through  the  exhibition  of 
the  above-named  factors  of  physical  properties?  In  my  opinion,  we 
are  not  warranted,  from  the  available  data,  so  to  judge.  This  does 
not  mean  flight  to  vitalism.  It  simply  means  that  there  is  among 
others  one  or  more  factors  as  yet  immeasurable  though  of  undoubtedly 
great  importance,  that  have  not  been  introduced  into  the  accounting. 
One  factor  is  the  physico-chemical  constitution  of  the  protoplasm  of  the 
epithelial  cells.  This  protoplasm  may  be  defined  as  a  fluid  lipo-protein- 
saline  complex.  While  from  one  point  of  view  it  is  to  be  regarded  as  a 
two-phase  system,  a  system  of  coexisting  phases,  from  another  point 
of  view  it  is  a  fluid.  It  is  a  structure  with  very  high  surface  tension, 
with  marked  capacity  for  adsorption  reactions,  with  a  pronounced 
tendency  to  chemical  reactions,  a  system  in  which  variations  in  the 
equilibrium  are  easily  produced.  The  physico-chemical  structure  of 
such  protoplasm  is  dependent  upon  its  life.  When  the  circulation 
ceases,  when  the  processes  of  oxidation  are  suspended,  when  the  reac- 
tions essential  to  its  function  are  suppressed,  its  state  of  equilibrium 
must  suffer  alteration.  From  the  purely  physico-chemical  point  of 
view,  the  constitution  of  the  protoplasm  must  change  with  death, 
because  when  withdrawn  from  the  conditions  of  metabolism  and 
function,  the  chemical  reactions  within  the  protoplasm  are  changed, 
and  consequent  upon  this  the  physico-chemical  state  of  the  proto- 
plasm must  be  altered.  Therefore,  one  ought  never  to  force  upon 
living  tissue  the  negative  conclusion  of  experiments  done  on  dead  tissue. 
This  influence  of  the  physico-chemical  constitution  of  the  epithelial 
cells  upon  the  processes  of  resorption  in  the  qualitative  sense  must 
not  be  overlooked.  It  is  possible  that  herein  lie  largely  the  qualita- 
tive differences  that  have  been  noted  between  purely  physical  resorp- 
tion under  the  conditions  of  experimentation  and  the  phenomena 
observed  during  life.  Most  of  the  differences  have  been  quantitative 
to  be  sure,  and  these  we  may  infer  lie  largely  in  the  incomplete  condi- 
tions of  our  methods  of  experimentation.  But  some  of  the  differences 
are  qualitative.  For  the  elucidation  of  the  qualitative  differences  it 
is  not  enough  to  study  the  qualitative  properties  of  the  substances 
to  be  resorbed;  valuable  as  these  data  are,  that  is  only  one  side  of  the 
matter.  Equally  important  is  the  physico-chemical  state  of  the  resorp- 
tion membrane.  For  certain  cell  membranes  it  is  known  that  they 
absolutely  bar  the  passage  of  otherwise  easily  diffusible  ions.  This 
exclusion  is  due  to  a  physico-chemical  property  of  the  cell  wall.  Proto- 
plasmic membranes  act  not  merely  as  physical  membranes  but  also 
as  reaction  surfaces.  When  a  solution  is  placed  upon  a  layer  of  proto- 
plasm, not  only  is  it  placed  upon  a  diffusion  membrane,  but  we  have 
in  effect  two  chemical  systems  placed  in  contact.  And  the  chemical 
and  physico-chemical  reactions  between  the  two  systems  may  modify 
greatly  the  phenomena  of  physical  diffusion,  in  both  qualitative  and 
quantitative  senses.  One  can  obtain  a  certain  experimental  insight  into 
this  matter  by  watching  the  processes  of  diffusion  through  a  detached 


204  DIGESTION 

serous  membrane.  As  the  membrane  dies,  its  properties  as  a  diffusion 
membrane  change.  These  changes  are  the  result  of  alterations  in  the 
chemical  and  physico-chemical  constitution  of  the  protoplasm  of  the  cells, 
due  to  the  withdrawal  of  circulation,  the  cessation  of  oxidation  and 
other  metabolic  reactions  and  to  the  fall  in  temperature.  It  is  this 
factor,  the  importance  of  which  we  are  just  beginning  to  appreciate 
and  the  experimental  definition  of  which  is  not  yet  possible,  that  has 
been  overlooked  in  past  endeavors  to  explain  intestinal  resorption 
upon  the  purely  physical  basis.  It  is  this  fact,  misinterpreted  and 
glorified  with  the  title  of  u  living,"  that  has  led  the  vitalist  to  reject  the 
conception  of  intestinal  resorption  as  a  physical  and  physico-chemical 
phenomenon.  There  is  no  known  fact  of  intestinal  resorption  that 
cannot  be  reasonably  explained  upon  the  basis  of  the  conception  of 
purely  physical  forces  operating  in  connection  with  a  membrane 
of  the  physico-chemical  properties  of  protoplasm;  the  complete  experi- 
mental reproduction  of  the  total  phenomenon  has,  however,  not  yet 
been  achieved.  But  to  consider  a  thing  in  experimental  science  as 
unachievable  because  in  the  incomplete  state  of  our  technique  not  yet 
achieved,  is  so  unscientific  as  to  border  on  absurdity. 


SUMMARY  OF  PATHOLOGICAL  VARIATIONS  IN  THE  PROCESSES 

OF   DIGESTION 

A  systematic  classification  of  the  disturbances  of  the  functions  of 
the  alimentary  tract  permits  of  the  possible  pathological  variations 
being  grouped  under  several  headings. 

Disturbances  due  to  improper  methods  of  mastication. 

Disturbances  due  to  toxic  or  otherwise  injurious  ingesta. 

Disturbances  due  to  anomalies  in  secretion  of  digestive  juices. 

Disturbances  due  to  abnormalities  in  motor  functions. 

Disturbances  due  to  qualitative  deviations  in  the  chemical  reactions 
of  the  processes  of  digestion. 

Disturbances  due  to  quantitative  variations  in  the  chemical  reactions 
of  the  digestive  processes. 

Disturbances  due  to  defects  in  the  processes  of  resorption. 

Disturbances  due  to  bacterial  infections  and  reactions  within  the  tract. 

While  this  treatise  is  not  designed  to  discuss  the  diseases  of  the 
alimentary  tract,  the  physiological  knowledge  now  at  our  command 
enables  us  to  make  a  survey  of  the  field  of  pathological  variations. 
The  ill  results  of  deficient  mastication  and  ensalivation  of  the  food 
are  fourfold.  The  trituration  is  not  adequate,  leaving  large  pieces 
of  food  to  be  passed  through  the  stomach  and  intestine.  This  is  of 
little  consequence  to  carnivora,  but  is  liable  to  be  followed  by  signs 
of  alimentary  distress  in  man.  The  lack  of  proper  ensalivation  makes 
more  difficult  the  attainment  of  an  adequately  emulsified  chyme  in 
the  stomach.    This  state  of  chyme  is  of  great  importance  to  intestinal 


PATHOLOGICAL   VARIATIONS  IN  PROCESSES  OF  DIGESTION     205 

digestion.  Mastication  tends  reflexly  to  increase  the  secretion  of 
gastric  juice,  a  fact  that  seems  to  hold  even  for  the  act  of  sucking  in  the 
infant.  Lastly,  lack  of  ensalivation  means  absence  or  deficiency  in 
the  salivary  enzymes.  This  is  probably  the  least  important  result, 
as  this  defect  is  easily  made  up  in  the  small  intestine.  The  stress  laid 
upon  the  importance  of  the  salivary  enzymes  in  the  modern  fad  of 
supermastication  is  not  justified  by  our  knowledge  of  their  scope  in 
the  total  processes  of  digestion.  But  trituration  and  ensalivation  are 
of  great  importance  to  the  chyme-forming  function  of  the  stomach. 

Disturbances  due  to  toxic  or  other  injurious  effects  of  the  ingesta, 
exogenous  intoxications  due  to  decomposition  of  foods,  lie  outside  the 
scope  of  this  treatise. 

The  variations  in  the  secretion  of  the  various  alimentary  juices 
have  been  considered  in  the  appropriate  sections.  Disturbances  due 
to  alterations  in  the  motor  functions  have  also  been  considered.  Apart 
from  neoplasms,  parasites,  and  bacterial  infections,  these  include  the 
majority  of  clinical  instances  of  alimentary  disturbances. 

Disturbances  due  to  qualitative  deviations  in  the  chemical  reactions 
of  the  processes  of  digestion  are  not  known.  So  far  as  we  know,  the 
chemical  reactions  are  accomplished  or  left  in  part  uncompleted;  there 
is  no  qualitative  deviation  with  the  evolution  of  an  abnormal  product 
of  digestion. 

Disturbances  due  to  quantitative  variations  in  the  chemical  reactions 
of  the  processes  of  digestion  are  frequent,  and  have  been  considered 
in  appropriate  sections.  The  variations  are  all  in  the  direction  of 
deficiency.  Conditions  outside  of  the  absence  of  digestive  juices  might, 
however,  conceivably  operate  to  frustrate  the  chemical  processes  of 
digestion.  This  in  itself  would  have  little  consequence  were  it  not 
for  the  favorable  conditions  for  the  development  of  bacteria  thus  pro- 
duced. The  usual  causes  of  deficiency  in  digestion  are  absence  of  one 
or  more  of  the  alimentary  secretions,  or  abnormal  bacterial  infections. 

Disturbances  due  to  defects  in  the  processes  of  resorption  are  not  of 
frequent  occurrence.  Strictly  speaking  we  mean  the  non-resorption 
of  the  normal  products  of  digestion.  The  seat  of  the  defect  may  lie 
in  the  intestinal  mucosa  or  in  the  retroperitoneal  lymphatic  system 
in  the  case  of  the  fats;  in  the  intestinal  mucosa  alone  in  the  case  of 
protein  and  sugar.  It  is  not  to  be  assumed  that  defects  in  resorption 
need  be  accompanied  by  microscopic  alterations  in  the  intestinal 
mucosa  demonstrable  by  present  methods.  On  the  other  hand,  resorp- 
tion may  be  normal  through  an  intestinal  mucosa  the  seat  of  extensive 
lesions.  Ulcerations  do  not  apparently  modify  to  any  extent  the  resorp- 
tion processes  of  the  intestine.  When  one  considers  the  phenomenon 
of  anaphylaxis,  one  is  led  to  wonder  why  sensitization  to  foreign  protein 
is  not  developed  in  the  subjects  of  gastric  or  intestinal  ulcer  by  resorp- 
tion of  unchanged  protein  through  the  ulcerated  area.  Possibly  such 
have  occurred,  the  source  of  sensitization  having  escaped  detection. 
Man  is  apparently  not  very  prone  to  anaphylaxis.     Nevertheless, 


206  DIGESTION 

instances  of  anaphylaxis  have  been  reported  in  children  following 
the  ingestion  of  protein,  especially  egg  albumin,  that  lead  one  to  infer 
that  sensitization  had  previously  occurred  through  alimentary  resorp- 
tion of  unaltered  protein.  How  this  resorption  was  accomplished  is 
not  known.  The  mucosa  of  the  alimentary  tract  of  newborn  animals 
has  been  experimentally  shown  to  be  permeable  to  foreign  proteins. 

Disturbances  due  to  bacterial  processes  in  the  alimentary  tract  are 
very  common,  and  deserve  a  detailed  consideration  that  lies  outside 
the  scope  of  this  work.  Bacteria  may  operate  in  three  directions: 
by  the  abstraction  of  nutrients  designed  for  the  organism,  a  factor 
that  may  be  disregarded;  by  the  formation  of  toxic  substances  from 
the  products  of  the  digestion  of  the  foodstuffs;  and  by  the  elaboration 
of  specific  poisons.  In  reality  the  bacterial  infections  of  the  alimentary 
tract  lead  to  specific  diseases,  only  a  few  of  which  are  yet  individually 
recognized  and  delineated.  What  is  commonly,  though  erroneously, 
termed  gastro-intestinal  auto-intoxication  (exogenous  intoxication 
being  excluded),  is  in  reality  bacterial  infection  and  intoxication,  not 
auto-intoxication.  It  is  as  incorrect  to  speak  of  an  intestinal  bacterial 
infection  as  an  auto-intoxication  as  to  term  hookworm  disease  an  auto- 
intoxication. Further  investigations  into  the  flora  of  the  intestine 
will  certainly  lead  to  the  definition  of  specific  disease  types,  due  to  the 
presence  of  specific  varieties  of  microorganisms.  Asiatic  cholera  is  an 
instance  of  an  exaggerated  intestinal  infection.  What  is  now  needed 
is  less  verbiage  concerning  symptomatology  and  more  concrete  work 
directed  to  the  study  of  the  bacterial  flora  of  the  intestinal  tract.  No 
instance  of  auto-intoxication  due  to  qualitative  perversion  or  quanti- 
tative variation  in  the  chemical  processes  of  digestion  has  ever  been 
reported,  unless  we  wish  to  term  hyperchlorhydria  an  auto-intoxica- 
tion. The  so-called  gastro-intestinal  auto-intoxications  are  bacterial 
infections  and  intoxications. 


GENERAL   RELATIONS    OF   HEAT    AND    ENERGY   IN   DIGESTION 

The  reaction  of  the  hydrolytic  cleavage  of  the  proteins,  fats,  and 
carbohydrates,  under  which  term  the  digestion  of  these  substances  is 
described,  is  practically  isothermic.  By  this  we  mean  that  no  heat 
is  lost  or  gained  in  the  reaction.  Oxidations  are  exothermic,  that  is, 
heat  is  set  free;  reductions  are  endothermic,  heat  is  combined.  Applied 
concretely  to  the  substances  of  digestion  and  their  products,  we  under- 
stand that  when  a  starch  is  converted  into  sugar,  the  sugar  has  about 
the  same  caloric  value  as  had  the  starch;  when  a  fat  is  split,  the  fatty 
acids  and  glycerol  have  about  the  same  heat  value  as  had  the  fat; 
when  a  protein  is  hydrolyzed,  the  amino-acids  have  about  the  same 
caloric  value  as  had  the  protein.  This  is  not  strictly  true,  but  the 
differences  are  slight.  The  invert  sugar  derived  from  the  hydrolysis 
of  a  unit  of  cane  sugar  yields  3  per  cent,  less  heat  than  does  the  cane 


GENERAL  RELATIONS  OF  HEAT  AND  ENERGY  IN  DIGESTION     207 

sugar.  The  loss  for  starch  is  difficult  of  measurement,  but  is  less  than 
5  per  cent.  The  loss  for  fat  is  5  to  7  per  cent.  The  loss  for  protein  is 
somewhat  greater,  though  not  accurately  known,  probably  under  10 
per  cent.  From  the  standpoint  of  the  chemical  reactions  of  digestion, 
therefore,  little  energy  is  lost  in  the  processes  of  alimentary  digestion. 
In  any  event,  the  total  process  would  be  an  absolutely  isothermic  one, 
since  the  end  products  of  digestion  (with  the  exception  of  glucose) 
are  in  the  processes  of  resorption  recombined.  Exactly  as  much  heat 
as  might  be  set  free  in  the  reactions  of  digestion  is  again  combined  in 
the  reactions  of  reconstruction.  The  end  products  of  the  digestion  of 
protein  and  fat  are  recombined  in  the  wall  of  the  intestine  to  form  the 
states  in  which  they  were  ingested,  protein  and  fat;  therefore,  the  total 
reaction  must  be  isothermic,  even  though  the  cleavage  reactions  them- 
selves were  exothermic. 

These  facts  of  the  heat  relations  of  the  chemical  processes  of  diges- 
tion are  diametrically  at  variance  with  the  widely  diffused  idea  that 
enzymic  action  involves  an  expenditure  of  energy.  It  cannot  be  too 
repeatedly  stated  that  the  reaction  of  fermentation  rests  upon  a  reduc- 
tion in  the  internal  chemical  resistance,  and  not  upon  an  increased 
outlay  of  energy.  It  is  not  more  work  done:  but  simply  the  same  work 
done  in  a  shorter  period  of  time. 

Because  no  heat  is  lost  in  the  chemical  reactions  of  cleavage  and 
reconstruction  in  the  processes  of  digestion,  it  would,  however,  be 
incorrect  to  conclude  that  no  work  is  done  in  the  act  of  digestion  con- 
sidered as  a  whole.  The  secretion  of  the  digestive  juices  entails  a  certain 
heat  production.  The  processes  of  resorption  are  associated  with  a  small 
loss  of  heat.  The  largest  factor  lies  unquestionably  in  the  muscular 
movements  of  the  alimentary  tract.  When  one  considers  the  masses 
of  food,  observes  the  churning  movements  of  the  stomach  and  the 
peristalsis  of  the  intestinal  coils,  it  is  clear  that  quite  a  little  work  is 
expended.  The  amount  of  heat  lost  in  these  processes  cannot  be 
measured.  It  may,  perhaps,  be  judged  to  lie  within  100  Calories  per 
day. 

This  loss  of  heat  is  not  to  be  confused  with  the  larger  production 
of  heat  associated  with  the  metabolism  following  the  ingestion  of  food. 
If  we  determine  the  caloric  needs  of  a  starving  individual,  and  then 
administer  in  food  (absorbed)  exactly  that  amount  of  calories,  it  will 
be  found  that  these  are  not  sufficient  to  support  the  heat  production; 
this  rises  following  the  ingestion  of  food,  and  the  individual  will  not 
be  in  caloric  equilibrium.  This  loss  of  heat  following  the  ingestion  of 
food  is  greatest  for  protein,  less  for  fat,  and  least  for  sugar.  This  heat 
production  is  due  to  what  is  termed  the  specific  dynamic  action  of  the 
foodstuffs,  an  action  greatest  for  protein  and  least  for  sugar.  The 
results  of  the  operation  of  this  specific  dynamic  action  of  the  foodstuffs 
(which  subject  will  be  detailed  in  another  chapter)  is  a  loss  of  heat 
in  the  processes  of  metabolism  following  digestion;  there  is  a  difference 
between  the  plane  of  maintenance  in  starvation  and  the  plane  of  main- 


208  DIGESTION 

tenance  in  feeding,  there  is  a  heat  production  associated  with  the  latter 
that  is  a  loss  to  the  body.  This  heat  production  varies  under  different 
conditions  of  external  temperature  and  with  different  diets;  it  may  be 
judged  to  vary  from  150  to  300  Calories  per  day  for  average  mixed  diets. 
This  is  a  much  greater  loss  than  that  which  occurs  in  association  with 
the  processes  of  alimentary  digestion.  It  should  be  clearly  understood 
that  although  this  larger  heat  production  follows  the  ingestion  of  food, 
the  loss  does  not  occur  within  the  alimentary  tract,  but  within  the 
metabolism  following  the  entrance  into  the  circulation  of  the  prod- 
ucts of  digestion.  There  is  a  small  primary  loss  of  heat  in  the 
processes  of  digestion;  there  is  a  larger  loss  of  heat  in  the  post-digestive 
metabolism. 

THE   FECES 

The  Mass  of  the  Feces. — The  mass  of  the  feces  depends  upon  three 
factors:  the  character  of  the  diet,  the  bacterial  processes  in  the  intes- 
tine, and  peristalsis.  When  all  three  operate  in  the  one  or  other  direction 
the  smallest  and  the  largest  bulks  of  feces  are  to  be  observed.  As  a 
rule,  the  content  of  resorbable  material  in  the  stools  is  inversely  pro- 
portional to  the  period  of  retention  in  the  small  intestine.  Colonic 
diarrhea  has  little  influence  on  resorption.  Under  pathological  conditions 
a  fourth  factor  may  be  added,  the  excessive  secretion  of  water  by  the 
intestinal  tract.  As  described  under  the  consideration  of  resorption 
in  the  intestine,  the  normal  function  is  the  resorption  of  water.  A 
small  amount  of  water  is,  of  course,  contained  in  the  succus  entericus, 
but  a  great  deal  more  water  is  resorbed.  Under  certain  conditions  of 
bacterial  infection  of  the  tract,  this  stream  may  be  reversed,  and  large 
amounts  of  water  eliminated;  and  to  the  withdrawal  of  water  from 
the  tissues,  many  of  the  most  prominent  symptoms  of  these  intestinal 
infections  are  to  be  attributed. 

The  weight  of  the  daily  milk  stool  of  an  adult  will  rarely  run  over 
50  grams.  The  weight  of  the  daily  stool  of  an  ordinary  mixed  diet 
may  vary  from  50  to  300  grams;  if  the  diet  consist  of  meat,  fats,  bread, 
and  dairy  products,  with  few  fresh  vegetables  or  fruits,  the  weight  will 
often  be  under  100  grams;  the  higher  the  proportion  of  fruits  and 
vegetables,  the  higher  the  weight  of  the  stools.  The  daily  stool  of  a 
vegetarian  or  a  fruitarian  may  weigh  a  half  kilo  or  even  more.  The 
increased  weight  of  the  stool  in  the  vegetarian  and  fruitarian  is  due 
partly  to  the  greater  amounts  of  indigestible  solids;  but  it  is  due  in 
part  to  the  greater  amount  of  unresorbed  digestible  solids,  and  to  the 
greater  content  of  bacteria  and  water.  The  more  frequent  is  defecation, 
upon  a  mixed  diet,  the  greater  the  weight  of  the  stool,  the  difference 
being  largely  water. 

The  water  of  the  feces  varies  with  the  diet,  the  bacterial  condition 
of  the  tract  and  the  frequency  of  defecation.  It  is  especially  high  in 
the  normal  milk  stools  of  children,  where  it  runs  from  80  to  90  per  cent. 


THE  FECES  209 

The  milk  stool  of  the  adult  is  much  more  solid.  Milk  and  meat  stools 
may  contain  no  more  than  50  per  cent,  of  water;  they  may  contain 
75  per  cent.  In  the  large  stools  of  the  vegetarian  or  fruitarian,  the  water 
content  is  often  high,  three-fourths;  but  one  may  see  the  stool  of  the 
same  diet  containing  less  than  one-half  water.  From  this  data  it  is 
clear  that  in  the  case  of  the  small  stools  of  a  milk  or  meat-fat-cereal 
diet,  the  water  output  of  the  intestinal  tract  may  be  as  low  as  25  grams ; 
whereas  in  the  case  of  a  vegetarian  or  fruitarian  diet,  the  water  output 
of  the  tract  may  be  as  high  as  500  grams.  The  meaning  of  such  varia- 
tions for  the  function  of  the  kidneys  is  obvious.  In  the  use  of  vegetables 
and  fruits  in  the  treatment  of  constipation,  one  secures  larger  stools, 
not  only  because  of  the  greater  mass  of  indigestible  material  and  un- 
resorbed  digestible  residue,  but  also  because  of  the  greater  water  content 
of  the  stools.  This  larger  water  content  is  doubtless  due  in  part  to  the 
greater  bacterial  activity  prevailing  in  large  mixed  stools.  The  water 
content  of  pathological  stools  may  be  very  high;  it  is  not  unusual  to 
find  watery  stools  that  contain  less  than  50  grams  of  solids  to  the 
liter. 

The  average  dried  weight  of  the  daily  stool  varies  from  15  to  50 
grams;  in  the  case  of  vegetarians  it  may  rise  to  over  100  grams  per  day. 
The  lowest  values  are  to  be  seen  in  meat-rice-fat  stools.  Ordinary 
average  dried  weights  present  less  fluctuation,  varying  from  20  to  40 
grams.  The  heat  value  of  dried  feces  varies  from  5  to  6.5  Cal.  per 
gram,  the  highest  values  being  seen  in  the  stools  of  milk  or  meat  diets. 

Peristalsis. — Under  the  term  peristalsis  we  group  the  muscular 
movements  of  the  intestine.  Though  not  usually  classed  together, 
the  movements  of  the  stomach  are  identical  in  physiological  meaning. 
Two  kinds  of  movements  are  to  be  observed:  (a)  Mixing  movements 
comprising  rotary  contractions  in  circumscribed  sections  of  the  intes- 
tines, combined  with  propulsive  and  reversed  movements.  For  both 
the  stomach  and  intestine,  localized  reversed  peristalsis  has  been 
observed  and  evidently  forms  part  of  the  normal  mechanism,  (b) 
Propulsive  movements,  by  which  the  contents  are  gradually  propelled 
toward  the  colon.  In  the  colon  only  propulsive  movements  occur, 
to  any  extent  at  least.  The  time  normally  required  to  propel  the  con- 
tents of  the  duodenum  to  the  upper  end  of  the  colon  varies  in  different 
individuals  from  four  to  twelve  hours,  or  even  more. 

The  obvious  functions  of  intestinal  peristalsis  are  four:  the  emulsifi- 
cation  of  the  contents,  this  being  greatly  aided  by  the  mucin  secreted 
by  the  intestine;  the  admixture  of  the  ferments  with  the  emulsified 
content  of  foodstuffs,  which  state  of  homogeneity  (using  the  term  in 
its  ordinary  meaning)  affords  to  the  ferments  the  maximum  surface 
contact  with  the  particles  of  foods;  shifting  of  the  contents,  whereby 
fresh  portions  are  successively  brought  into  contact  with  the  resorption 
membrane;  and  the  removal  of  the  gases  of  bacterial  decomposition, 
the  accumulation  of  which  would  soon  lead  to  dilatation  and  paralysis 
of  the  muscular  coats  and  inhibition  of  resorption.  It  is  difficult  to 
14 


210  DIGESTION 

overestimate  the  importance  of  the  functions  of  gastric  and  intestinal 
peristalsis;  there  is  far  more  disease  of  the  alimentary  tract  due  to 
disturbances  of  motility  than  to  disorder  of  chemical  action  in  diges- 
tion; while  there  are  several  ways  of  chemical  action,  there  is  but  one 
motility.  The  crucial  importance  of  peristalsis  for  the  processes  of 
resorption  may  be  shown  in  a  simple  experiment.  To  ordinary  gastric 
contents,  or  to  the  contents  of  the  small  intestine,  properly  emulsified, 
a  known  amount  of  an  easily  diffusible  substance  like  glucose  is  added, 
and  the  mass  placed  in  a  dialyzer.  For  the  first  few  minutes,  the  dif- 
fusion of  the  sugar  will  be  rapid,  then  it  will  fall  quickly  to  a  minimum. 
In  such  a  thick  viscid  mass,  convection  streams  do  not  occur.  And 
thus  after  the  first  few  moments,  the  velocity  of  dialysis  will  be  reduced 
to  the  velocity  of  the  diffusion  of  the  sugar  through  the  mass  of  the 
contents  to  the  line  of  membrane,  a  slow  process.  If,  however,  the 
mass  of  contents  be  regularly  and  vigorously  stirred,  diffusion  will 
remain  rapid,  up  to  a  certain  point  proportional  to  the  vigor  of  stirring. 
In  each  moment  the  peristalsis  of  the  intestine  removes  from  the  epi- 
thelial layer  the  contents  whose  products  of  digestion  have  been 
resorbed,  and  places  thereon  a  fresh  layer  of  maximum  concentration, 
thus  affording  to  the  resorptive  surface  the  fullest  opportunity  for 
functionation. 

Normal  intestinal  peristalsis  is  probably  a  function  which  when 
once  set  into  operation  by  the  passage  of  food  into  the  duodenum  is 
automatic  and  self-regulatory  within  wide  limits,  decreasing  gradually 
as  the  mass  of  the  contents  passing  down  the  tract  becomes  reduced 
in  volume.  Diet  has,  of  course,  some  influence  upon  it.  A  large  amount 
of  fat  in  the  diet  tends  to  stimulate  peristalsis.  And  the  presence  of 
large  masses  of  indigestible  residue  tends  to  accelerate  peristalsis. 
Many  chemical  substances  also,  such  as  the  organic  acids  in  fruits  and 
vegetables,  act  as  stimulants  or  irritants.  There  can  be  no  question 
that  bacterial  processes  are  of  importance,  and  that  with  certain  flora 
peristalsis  may  be  greatly  stimulated.  But  on  the  whole,  with  normal 
diets  and  in  health,  it  is  an  automatic  function,  quite  independent  of 
the  momentary  contents  of  the  tract. 

With  the  colon  it  is  clearly  different.  The  study  of  the  intestinal 
contents  and  habits  of  defecation  of  animals  illustrates  clearly  that 
colonic  peristalsis  is  proportional  to  the  mass  of  colonic  contents. 
The  physical  irritation  of  the  indigestible  residue  (upon  which,  for 
example,  the  laxative  action  of  figs  and  of  coarse  oatmeal  depends), 
and  the  chemical  irritation  of  the  products  of  bacterial  action  (promi- 
nent in  the  herbivora)  are  factors  to  be  sure;  but  on  the  whole,  the  mass 
of  colonic  contents  determines  frequency  of  defecation.  The  system  of 
daily  defecation  in  man  represents  the  attempt  to  establish  a  different 
rule  for  the  colon.  The  carnivora  do  not  defecate  daily.  Nor  would 
man  defecate  daily  on  a  concentrated  diet  of  meat,  fat,  bread,  milk, 
and  cheese.  When  one  considers  the  size  of  a  stool  of  50  grams  weight 
and  contrasts  it  with  the  capacity  of  the  colon,  it  is  clear  that  if  the 


THE  FECES  211 

peristalsis  of  the  colon  were  related  only  to  the  mass  of  the  feces,  daily 
defecation  would  not  occur;  such  a  small  stool  is  almost  lost  in  the 
colon.  If  defecation  be  desired  daily,  the  mass  of  the  stools  must  be 
increased  or  the  colon  must  be  given  a  different  rule  of  action,  the 
habit  of  periodicity.  Without  distention,  the  normal  colon  holds  6 
kilos  of  water,  the  sigmoid  flexure  alone  more  than  1  kilo.  The  amount 
of  feces  found  in  the  colon  in  cases  of  sudden  death  from  accident 
vary  from  half  a  kilo  up  to  2  kilos.  An  impacted  colon  ma}'  contain 
5  kilos  of  feces ;  in  the  extreme  cases  of  colonic  dilatation,  which  is  what 
the  "balloon  men"  of  the  circus  are,  the  capacity  is  almost  beyond 
credence. 

The  time  relation  between  the  ingestion  of  a  food  and  the  discharge 
of  the  stool  representing  it,  is  quite  variable.  The  marking  of  the 
stools  in  metabolic  investigations  has  given  good  data  on  this  point. 
If  charcoal  be  given  with  a  breakfast,  it  may  rarely  be  recovered  on  the 
same  evening.  In  a  goodly  number  of  individuals,  it  will  be  recovered 
on  the  next  morning,  after  twenty-four  hours.  In  the  majority  of 
individuals  it  will  be  recovered  on  the  second  morning,  after  forty- 
eight  hours.  Sometimes  it  will  not  be  recovered  until  the  third  or  even 
fourth  day,  in  individuals  in  perfect  health  and  with  daily  evacuation 
of  the  bowels.  Whether  an  individual  will  pass  the  charcoal  stool  in 
twenty-four,  forty-eight,  or  seventy-two  hours,  depends  not  upon  the 
retention  of  the  food  in  the  stomach  or  small  intestine,  but  upon  the 
duration  of  retention  in  the  colon.  Some  colons  keep  quite  empty; 
others  tolerate  an  amount  of  feces  representing  the  diet  of  several 
days.  Within  reasonable  limits,  the  one  state  of  affairs  cannot  be 
termed  more  normal  than  the  other. 

Reaction  of  the  Feces. — The  reaction  of  normal  feces  may  be  neutral, 
faintly  alkaline  or  faintly  acid.  The  milk  stools  of  infants  are  usually 
acid.  The  degrees  of  acidity  or  alkalinity  involved  in  normal  feces 
is  very  slight.  Abnormally,  excesses  of  acidity  are  common,  both  in 
children  and  in  adults,  due  to  acids  formed  through  bacterial  action. 

Odor  of  the  Feces. — The  substances  to  which  feces  owe  their  odor 
under  different  circumstances  are  only  known  in  part.  They  are  prob- 
ably all  of  bacterial  origin.  Hydrogen  sulphid,  mercaptans,  methane, 
indol,  skatol,  and  volatile  fatty  acids  are  the  substances  normally 
most  concerned  in  the  fecal  odor.  Their  derivation  will  be  discussed 
under  bacterial  processes  in  the  digestive  tract. 

The  gases  of  the  intestinal  tract,  apart  from  carbon  dioxid  and 
nitrogen  that  remain  unabsorbed  when  swallowed,  are  also  derived 
from  the  bacterial  reactions.  They  include  hydrogen,  hydrogen  disul- 
phid,  methane,  mercaptans,  phosphin,  and  traces  of  primary  alcohols. 
The  constitution  of  these  gases  testifies  directly  to  the  very  slight 
occurrence  of  oxidations  in  the  intestinal  tract.  The  carbon  dioxid  is 
derived  from  the  blood  and  from  alcoholic  fermentation. 

The  feces  contain  many  substances  of  bacterial  derivation,  which 
will  be  considered  in  the  section  devoted  to  that  subject.    They  include 


212  DIGESTION 

many  members  of  the  series  of  fatty  acids,  unsaturated  acids,  alcohols, 
amino-acids,  derivations  of  the  benzene  ring,  and  mixed  compounds. 

Solids  of  the  Feces. — Indigestible  Residue  of  the  Diet. — This 
will  vary  from  nothing,  in  the  case  of  milk  diet  to  as  high  as  60  or  70» 
grams  per  day  in  the  case  of  the  diet  of  vegetarians  or  fruitarians. 
Under  this  heading  are  included  cellulose,  connective  tissue,  skins 
and  coverings,  seeds,  gums,  and  resins,  pectins,  chlorophyl,  chitins — 
varying  obviously  with  the  diet.  The  indigestible  residue  of  an  average 
mixed  diet  will  not  usually  exceed  10  grams  per  day. 

Bacteria. — By  means  of  centrifugation  it  is  possible  in  an  approxi- 
mate manner  to  separate  the  bacteria  from  the  other  solids  of  the 
stools.  The  results  of  such  segregations  have  taught  us  the  surprising 
fact  that  from  one-fourth  to  one-half  of  the  dried  residue  of  feces  con- 
sists of  the  bodies  of  bacteria.  In  other  words,  in  the  stools  of  a  day, 
from  5  to  20  or  even  more  grams  (dried  weight)  of  bacteria  will  be 
discharged.  High  figures  are  obtained  for  the  milk  stools  of  children, 
due  to  the  luxuriant  proliferation  of  the  lactic-acid  group.  High  figures 
are  also  contained  in  the  large  stools  of  vegetarian  diet,  rather  low 
counts  being  often  noted  in  the  small  stools  of  a  concentrated  meat- 
fat-bread  diet.  Since  these  bacteria  are  in  large  part  purely  sapro- 
phytic germs,  there  is  no  necessary  relationship  between  the  counts 
and  fermentative  activity  within  the  intestinal  cavity.  The  larger 
proliferation  occurs  undoubtedly  within  the  colon. 

Residue  of  Digestible  Food. — This  exists  in  two  forms:  food 
that  has  escaped  the  chemical  action  of  the  digestive  juices,  and  food 
that  has  been  digested  but  not  resorbed. 

For  the  carbohydrates,  the  first  alone  is  normally  found,  if  at  all. 
The  digestibility  of  carbohydrates  depends  largely  on  proper  cooking. 
If  starchy  foods  be  imperfectly  cooked,  or  if  unmasticated  though 
properly  cooked  (as  in  the  swallowing  of  whole  rice,  beans,  or  oats), 
they  may  pass  undigested  into  the  feces.  The  same  holds  good  of 
improperly  made  bread.  When  starches  and  grains  are  properly 
cooked  and  masticated,  it  is  not  usual  to  find  undigested  remnants 
in  the  stools.  All  sugar  formed  from  starch  is  either  resorbed  or  falls 
a  prey  to  bacterial  fermentation,  none  is  found  in  the  stools.  For  the 
proteins,  both  forms  are  to  be  found;  undigested  fiber  of  meats,  and 
traces  of  peptone,  peptids,  and  amino-acids.  With  proper  cooking 
and  mastication,  few  meat  fibers  are  to  be  found  in  the  feces,  except 
in  the  absence  of  pancreatic  juice.  The  amount  of  peptid  and  amino- 
acids,  determined  by  methods  that  have  not  much  certainty  or  accuracy, 
usually  falls  below  one  gram,  calculated  from  the  nitrogen  content. 
Such  amino-acids  as  are  not  resorbed  are  subject  to  deaminization 
by  the  intestinal  bacteria. 

Nitrogen. — The  total  nitrogen  of  feces  may  vary  from  0.5  to  1.5 
gram  per  day,  on  a  ration  of  75  to  100  grams  of  protein.  The  percentage 
of  nitrogen  in  the  moist  stool  or  dried  feces  has  little  meaning;  it  is 
the  actual  amount  per  day  that  is  important.    This  nitrogen  is  divided 


THE  FECES  213 

into  several  fractions:     the  undigested  proteins  of  the  diet;  the  un- 
resorbed  amino-acids  of  the  diet;  the  unresorbed  amino-acids  of  the 
diet  transformed  by  bacteria;  the  nitrogen  of  the  mucin  and  nucleo- 
proteid  of  the  alimentary  secretions;  the  nitrogen  of  the  biliary  con- 
stituents.   It  is  not  possible  to  even  attempt  to  divide  into  these  several 
fractions  the  figures  for  nitrogen  obtained  for  stools  by  the  Kjeldahl 
method.    It  may  be  fairly  stated  that  with  mixed  diets  the  nitrogen 
of  the  mucin,  the  nucleoproteid,  the  bile,  and  the  bacteria  exceeds  the 
nitrogen  of  the  undigested  and  unresorbed  protein.     This  fact  is  too 
often  overlooked  in  the  interpretation  of  the  nitrogen  data  for  input 
and  output  in  metabolic  experiments.    If  any  material  portion  of  the 
mucin  secreted  by  the  intestinal  tract,  estimated  at  some  20  grams  per 
day,  were  discharged  with  the  feces,  this  ratio  would  be  much  higher; 
but  the  larger  part  of  this  mucin  is  digested  and  resorbed.    Normally 
coagulable  protein  and  proteoses  are  not  present  in  the  stool.    A  goodly 
part  of  the  nitrogenous  constituents  of  the  bile  are  resorbed,  the  amounts 
respectively  resorbed  and  eliminated  in  the  stools  being,  however, 
not  capable  of  estimation.    If  the  diet  consists  of  meat,  carbohydrate, 
and  fat,  the  nitrogen  of  the  stools  will  be  so  little  as  to  suggest  that 
it  represents  solely  the  residues  of  the  alimentary  secretions,  apart 
from  bacterial  bodies.    Such  feces  may  contain  no  more  than  half  a 
gram  of  nitrogen  per  day.    The  feces  of  a  man  in  starvation  contain 
nearly  as  much,  usually  about  a  third  of  a  gram.  The  stool  in  starvation 
may  contain  a  higher  percentage  of  nitrogen  than  the  stool  of  a  diet. 
The  stools  contain  on  a  sugar  diet  nearly  as  much  nitrogen  as  on  a 
meat  diet  if  the  latter  is  properly  digested.    It  is  clear  that  under  the 
most  ideal  conditions,  the  nitrogen  of  the  stools  is  little  more  than  the 
nitrogen  of  the  unresorbed  alimentary  secretions.    A  meat  diet  stimu- 
lates the  alimentary  secretions  to  a  greater  extent  than  does  a  sugar 
diet,  and  this  will  explain  the  slightly  greater  nitrogen  content  seen 
in  the  stools  of  meat  diet.    It  is  with  mixed  diets  that  we  observe  much 
larger  figures  for  the  nitrogen  of  the  feces.    So  soon  as  vegetables  and 
fruit  enter  into  the  diet  in  considerable  amounts,  the  resorption  of  the 
products  of  digestion  of  protein  falls.    This  is  in  all  probability  largely 
a  physical  condition;  the  undigestible  residue  of  cellulose,  etc.,  hinders 
the  functions  of  peristalsis,  so  that  the  entire  contents  of  the  intestine 
are  not  brought  into  contact  with  the  mucous  membrane  and  as  a  conse- 
quence resorption  is  not  complete.    Another  reason  may  lie  in  the  fact 
that,  as  a  rule,  the  stools  of  a  mixed  diet  lie  in  the  small  intestine  a 
shorter  time  than  do  the  stools  of  a  meat  and  starch  diet.    The  milk 
stool  of  adults  contains  more  nitrogen  than  the  meat  stool.    Infants 
utilize  the  casein  in  milk  better  than  do  adults.     But  adults  utilize 
the  fat  better  than  do  infants.    In  the  case  of  infants,  the  fat  is  largely 
in  the  state  of  neutral  fat,  suggesting  that  the  lipase  secretion  of  the 
pancreas  is  not  as  developed  in  infants  as  is  the  trypsin  secretion. 

From  these  data  it  is  evident  that  a  normal  subject  should  resorb 
at  least  85  per  cent,  of  the  protein  of  a  normal  diet.    This  figure  may 


214  DIGESTION 

rise  to  90  or  even  95  per  cent.,  and  may  exceptionally  fall  in  subjects 
in  full  health  to  80  per  cent.  It  must  be  kept  clearly  in  mind  that  these 
figures  hold  only  for  normal  rations  of  protein.  There  is  no  question 
that  with  very  heavy  rations  of  protein,  lower  resorption  may  be 
observed.  It  varies  also  with  the  form  of  protein.  It  has  been  often 
noted  that  resorption  on  a  milk  diet  is  less  than  in  the  case  of  meat. 
And  in  the  vegetarian,  resorption  may  be  notably  lower. 

The  normal  stools  do  not  usually  contain  any  protein  precipi table 
by  salts.  Polypeptids  and  amino-acids  are,  of  course,  always  present 
in  the  amounts  previously  stated. 

Pathologically,  much  larger  amounts  of  unresorbed  protein  or  nitrogen 
are  often  to  be  encountered.  The  ways  in  which  different  pathological 
conditions  operate  to  bring  about  this  result  may  be  grouped  under 
three  heads:  diarrhea;  lack  of  digestion,  due  to  absence  of  ferment;  and 
disease  of  the  resorptive  membrane.  Diarrhea  acts  in  itself  by  so 
reducing  the  stay  of  the  food  in  the  intestine  as  to  give  the  intestinal 
juices  little  time  to  accomplish  the  reactions  of  cleavage  and  to  permit 
of  resorption.  In  proportion  to  the  violence  of  the  diarrhea,  the  food 
reappears  more  or  less  unchanged.  It  is  not  uncommon  to  find  food 
discharged  within  an  hour  of  the  time  of  ingestion,  of  course,  quite 
unaltered.  Apart  from  this,  however,  diarrhea  acts  by  disturbing  the 
quality  of  the  succus  entericus  and  also,  apparently,  by  modifying 
the  normal  flow  of  pancreatic  secretion. 

The  absence  of  the  gastric  secretion  has  usually  no  effect  upon  the 
fecal  nitrogen,  the  digestion  of  protein  is  fully  accomplished  by  the 
intestinal  and  pancreatic  juices.  The  absence  of  pancreatic  juice  may 
result  in  no  disturbance  of  normal  digestion,  if  the  diet  be  well  arranged 
and  the  ration  of  protein  be  not  excessive.  It  may  result  in  a  marked 
increase  in  the  undigested  and  unresorbed  protein.  The  defect  lies 
in  chemical  digestion,  not  in  resorption;  such  protein  as  is  digested  is 
resorbed. 

In  diseases  of  the  intestinal  mucosa,  pronounced  reduction  in  resorp- 
tion may  result.  In  some  cases  of  pernicious  anemia,  in  enterocolitis 
of  infants,  in  tubercular  enteritis,  one  may  find  in  the  stools  large 
amounts  of  amino-acids,  the  protein  of  the  diet  having  been  digested 
by  the  gastric  and  pancreatic  juices  far  in  excess  of  the  faculty  of 
resorption.  In  other  cases,  however,  where  on  later  autopsy  the  intes- 
tinal mucosa  has  presented  widespread  signs  of  advanced  degeneration 
and  atrophy,  the  resorption  was  entirely  normal.  It  is  never  possible 
by  a  histological  examination  to  determine  to  what  extent  the  disease 
of  the  mucous  membrane  of  the  intestine  might  have  disturbed  its 
powers  of  resorption.  That  the  total  intestinal  lining  is  in  excess  of 
the  normal  needs  of  the  body,  thus  permitting  a  leeway  and  compensa- 
tion, is  shown  in  the  results  of  operative  experiments  on  the  intestine, 
by  means  of  which  portions  of  the  gut  are  switched  out  of  function. 
If  one-third  of  the  intestine  be  circuited  out  of  function,  there  is  no 
resultant  disturbance  in  the  utilization  of  foodstuffs.    When,  however, 


THE  FECES  215 

two-thirds  of  the  length  of  the  intestine  are  switched  out  of  function, 
there  is  a  moderate  reduction  in  the  utilization  of  protein,  a  marked 
reduction  in  the  utilization  of  fat,  with  no  disturbance  in  the  digestion 
of  carbohydrate.  Half  the  length  of  the  intestine  seems  capable  of 
permanently  sustaining  life.  This  is  made  all  the  more  sure  because 
the  villi  hypertrophy  after  resection  of  a  large  portion  of  the  intestine. 

Surveying  the  whole  field  of  diseases  of  the  digestive  tract  and  its 
accessory  glands,  one  must  be  struck  with  the  rarity  of  reduction  in 
the  digestion  and  resorption  of  protein  so  marked  as  to  threaten  the 
maintenance  of  the  nitrogenous  balance  of  the  body.  Such  a  state  of 
affairs  is  almost  unknown,  if  indeed  it  has  ever  been  shown  in  an  individ- 
ual properly  dieted,  and  not  the  subject  of  uncontrollable  diarrhea. 
The  man  with  cholera,  of  course,  does  not  digest  enough  protein  to 
maintain  nitrogenous  balance;  the  man  with  pyloric  obstruction  often 
does  not  digest  enough  protein  to  maintain  nitrogen  balance.  But  in 
such  instances,  if  food  can  be  gotten  into  the  intestine  and  retained 
there,  a  sufficient  digestion  would  occur.  Apart  from  such  very  excep- 
tional conditions,  protein  starvation  through  non-digestion  is  practically 
unknown. 

Fat. — In  the  normal  stool,  fat  exists  in  two  forms:  digested,  or  split; 
and  undigested,  as  neutral  fat.  On  a  fat  ration  of  100  grams,  from 
2  to  10  grams  may  be  found  in  the  stools.  With  larger  rations,  the 
amounts  tend  to  rise,  to  maintain  the  same  ratio.  Just  how  much  of 
this  fat  is  split  and  how  much  is  undigested,  varies  with  different  individ- 
uals. We  have  not  much  data;  until  recently  the  methods  of  analysis 
have  been  unsatisfactory.  Frequently  one  finds  the  split  fat  exceeding 
the  neutral  fat;  that  is,  the  fault  is  more  one  of  resorption  than  of 
digestion.  The  fats  of  high  melting  points  are  less  well  digested  than 
fats  of  low  melting  point.  A  larger  amount  of  fat  is  often  to  be  found 
with  a  milk  diet  than  with  a  mixed  diet.  Occasionally,  one  meets  with 
normal  individuals  who  on  a  ration  of  100  grams  of  fat  will  discharge 
as  much  as  20  grams  in  the  stools;  such  cases  are,  however,  rare,  and 
the  figure  stated  may  be  taken  as  the  highest  normal  limit.  Some  of 
the  fatty  bodies  of  the  feces  are  derived  from  the  alimentary  secretions, 
from  the  bile  and  succus  entericus;  the  amount  is  not  determinable, 
but  is  certainly  not  small.  The  stools  in  starvation  are  notably  rich 
in  fat,  and  the  stools  on  a  rice-meat  diet  may  contain  more  fat  than 
the  diet.  These  statements  hold  for  true  fat  and  are  not  a  fictitious 
result  due  to  the  presence  of  numerous  other  ether-soluble  substances 
in  the  stools.  The  fat  of  the  stools  has  a  higher  melting  point  than  the 
fat  of  the  diet,  due  apparently  to  relatively  low  resorption  of  tristearin. 

The  separation  of  fatty  acids  and  soaps  has  little  meaning,  resting 
upon  a  chemical  misconception.  What  we  need  to  know  may  be  stated 
under  two  questions:  How  much  of  the  known  fat  of  a  diet  was  split 
indigestion?  How  much  of  the  digested  fat  was  resorbed  ?  The  figures 
for  neutral  fat  and  total  fatty  acid  of  higher  fats,  answer  these  questions. 
How  much  of  these  fatty  acids  appear  in  the  form  of  soaps,  has 


216  DIGESTION 

nothing  to  do  with  the  functions  of  digestion  or  resorption,  but  is  quite 
accidental.  If  the  diet  contains  cations  in  scarcity  or  in  plenty,  if  the 
calcium  and  phosphoric  acid  elimination  of  the  small  intestine  are  so 
and  so,  more  or  less  of  the  fatty  acids  will  be  discharged  as  soaps.  The 
variables  that  determine  the  amount  of  soap  do  not  lie  at  all  in  the 
function  of  digestion. 

If  the  bile  be  absent,  the  fats  may  be  normally  digested  and  resorbed. 
If  any  defect  appear,  which  is  not  the  rule  with  a  normal  and  selected 
diet,  the  defect  will  usually  lie  in  resorption,  i.  e.,  the  stools  will  con- 
tain the  normal  amount  of  neutral  fat  but  an  excess  of  fatty  acids. 
Rarely,  the  neutral  fat  may  be  increased  also. 

If  the  pancreatic  juice  be  absent,  disturbance  in  the  digestion  of 
fat  is  likely  to  appear  with  a  normal  and  selected  diet.  The  amount 
of  neutral  fat  will  be  increased,  often  greatly;  the  amount  of  fatty  acid 
will  usually  be  normal.  With  a  diet  poor  in  fat,  the  digestion  may  be 
normal;  an  excess  of  neutral  fat  will  usually  appear  on  increasing  the 
fat  of  the  diet.    Some  cases  digest  normally  large  rations  of  fat. 

If  both  the  bile  and  pancreatic  juice  be  absent,  as  is  sometimes  seen 
in  lesions  affecting  the  papilla  of  the  duodenum  or  the  common  opening 
of  the  ducts,  digestion  and  resorption  will  usually  be  greatly  reduced; 
often,  however,  no  more  than  the  usual  amount  of  fatty  acid  will  be 
present  in  the  stool  that  is  loaded  with  neutral  fat.  One  must  not  be 
surprised,  however,  to  find  a  normal  digestion  of  say  50  grams  of  fat 
per  day  in  the  complete  absence  of  bile  and  pancreatic  juice. 

Ten  grams  of  fat  or  fatty  acid,  present  in  a  stool  of  50  or  75  grams 
in  weight,  lends  to  the  stool  a  macroscopic  appearance  of  fat,  especially 
when  the  stool  is  cold.  It  is,  however,  not  possible  to  judge  of  the 
fat  content  of  a  stool  by  inspection.  It  must  be  furthermore  insisted 
upon  that  to  form  a  reliable  judgment,  the  fat  in  the  diet  must  be 
known  and  controlled,  and  the  test  should  extend  over  a  number  of 
days. 

Biliary  and  Intestinal  Secretion. — The  feces  contain  the  remains  of 
the  biliary  and  intestinal  secretions.  Unknown  amounts  of  cholesterol, 
biliary  acids,  pigments,  and  lipoids,  and  of  mucin  are  normally  present. 
The  cholesterol  and  lipoids  are  usually  weighed  with  the  total  neutral 
fat,  which,  unless  corrected  by  a  determination  of  the  acid-number, 
will  lead  to  a  faulty  result,  though  no  great  error  would  be  possible. 
The  bile  pigment  is  usually  present  in  the  form  of  urobilin  or  in  other 
reduced  state.  Bilirubin  or  biliverdin  may,  however,  be  rarely  present 
in  normal  feces.  In  cases  of  diarrhea  the  unaltered  pigment  is  very 
likely  to  be  present. 

The  Color  of  the  Feces. — The  color  of  the  stools  is  due  to  three  different 
factors:  the  diet,  bacterial  processes,  and  the  biliary  pigments.  The 
bile  does  no  usually  determine  the  color.  Milk  gives  a  pale-yellow 
stool  in  infants,  but  in  adults  the  milk  stools  are  usually  more  deeply 
colored.  Meats  lend  a  dark  or  blackish  color,  due  to  reduced  hemo- 
globin pigments  and  sulphid  of  iron.    Many  vegetables  turn  the  stools 


PRODUCTS  OF  BACTERIAL  ACTION  ON  FOODSTUFFS       217 

black.  With  a  mixed  diet  the  colors  vary  from  deep  yellow  to  dark 
brown.  Green  stools  are  sometimes  to  be  seen  in  adults  or  children 
in  health  on  a  mixed  diet.  White  stools  are  sometimes  to  be  seen  in 
health,  due  to  the  reduction  of  bilirubin  to  a  leukourobilin.  Many 
variations  in  the  color  of  stools  can  be  shown  to  be  independent  of  the 
bile  or  any  article  in  the  diet,  and  for  these  we  hold  bacterial  processes 
of  unknown  nature  responsible. 


PRODUCTS    OF    BACTERIAL    ACTION    ON    FOODSTUFFS 

Bacteria  acts  upon  the  food  in  the  stomach  to  no  demonstrable  extent 
normally;  bacterial  action  in  the  small  intestine  is  normally  demon- 
strable. It  is  in  the  colon,  however,  that  bacteria  displays  their  most 
striking  activity.  The  immunity  to  bacterial  decomposition  enjoyed 
normally  by  food  in  the  stomach  is  due  in  part  to  the  brief  stay  there, 
to  the  fact  that  the  foods  are  but  slightly  digested  in  the  stomach 
(bacteria  operate  actively  upon  the  products  of  digestion  rather  than 
upon  native  foods),  and  to  the  action  of  hydrochloric  acid.  Whatever 
action  on  foods  is  to  be  noted  in  the  stomach,  even  under  pathological 
conditions,  is  usually  confined  to  fermentation  of  sugars.  Putrefaction 
is  rare,  even  in  diseases  of  the  stomach,  unless  the  foods  are  very  unduly 
retained  there  by  pyloric  stenosis  or  dilatation  of  the  viscus,  and  in 
particular  in  connection  with  ulcerative  carcinoma.  In  the  small 
intestine,  the  processes  of  digestion  and  resorption  proceed  with  such 
rapidity  that  the  bacteria  have  little  opportunity  to  act  upon  the  larger 
fraction  of  the  foods.  Upon  the  unresorbed  residues,  however,  and 
upon  the  alimentary  secretions  themselves,  bacteria  operate  in  a  pro- 
nounced manner.  Neither  the  bile  nor  any  other  intestinal  secretion 
is  today  regarded  as  endowed  with  notable  antiseptic  properties.  The 
hydrochloric  acid  is  indirectly  more  effective  in  the  repression  of  intes- 
tinal bacterial  action  than  are  the  bile  and  intestinal  secretions  directly. 
The  normal  chemical  action  of  the  hydrochloric  acid  (and  pepsin)  in 
the  gastric  digestion  so  accelerates  the  later  proteolytic  action  of  the 
trypsin  and  erepsin  as  to  depress  bacterial  action  by  removing  the 
media  of  their  development.  In  a  certain  sense,  the  alimentary  secre- 
tions may  be  said  to  furnish  more  nutriment  to  bacteria  than  do  the 
unresorbed  residues  of  the  products  of  the  digestion  of  the  foods.  The 
mucin  secreted  by  the  tract  amounts  to  probably  20  grams  per  day. 
The  pancreatic  juice  is  rich  in  protein  and  very  fermentable.  The 
bile  is  easily  decomposed,  and  as  elsewhere  stated,  most  of  the  constit- 
uents of  the  bile  are  greatly  modified  by  bacterial  action  in  the  tract. 
The  results  of  the  activities  of  bacteria  on  these  alimentary  secretions 
are  well  seen  in  starvation.  Intestinal  putrefaction  does  not  cease 
in  starvation.  On  the  contrary,  after  the  first  few  days  the  signs  of 
intestinal  putrefaction  in  the  urine  and  feces  indicate  that  the  bacteria 
in  the  intestine  are  very  active.    The  substrate  of  their  operations  is 


218  DIGESTION 

the  protein  of  the  alimentary  secretions.  These  proteins  are  apparently 
rich  in  phenyl-amino-acids  and  tryptophan,  as  phenol  and  indol  com- 
pounds are  prominent  in  the  urine  and  feces  of  the  starving  individual. 
The  action  of  bacteria  under  these  conditions  is  heightened  by  the 
presence  of  constipation.  And  though  we  must  believe  that  the  mass 
of  alimentary  secretions  is  much  reduced  in  the  state  of  starvation, 
their  prolonged  retention  in  the  lower  intestinal  tract  affords  to  bacteria 
full  opportunity  for  action.  Anaerobic  bacteria  are  now  regarded  as 
chiefly  responsible  for  putrefactive  processes  in  the  intestine. 

The  fermentation  of  carbohydrates  in  the  intestine  leads  to  the 
formation  of  lower  fatty  acids  and  alcohols,  lactic  and  succinic  acids; 
and  to  the  evolution  of  carbon  dioxid,  methane,  hydrogen,  and  other 
hydrocarbon  gases.  Raw  starch  that  has  escaped  digestion  usually 
escapes  bacterial  decomposition.  If  cooked  starch  escapes  digestion, 
as  is  often  the  case  in  improperly  prepared  foods,  it  will  often  be  found 
in  the  stools.  In  the  human  intestine  the  fermentation  of  starch  and 
cellulose  is  normally  very  restricted.  On  the  other  hand,  it  may  be 
regarded  as  certain  that  all  sugar  that  is  unresorbed  is  completely 
fermented  in  the  intestine.  There  is  evidence  that  in  different  diseases 
of  the  alimentary  tract,  especially  in  children,  abnormal  flora  may 
predominate,  with  the  production  of  abnormal  types  of  fermentation 
of  carbohydrates. 

The  fats  are  very  resistant  to  fermentation  in  the  intestine,  and  even 
under  pathological  conditions  it  is  rare  to  find  an  active  fermentation 
of  fat.  There  is  no  foundation  for  the  fear  that  an  acidosis  may  be 
caused  by  the  formation  of  the  ketonic  acids  from  fatty  acid  in  the 
intestine.  It  is  true  that  in  many  cases  of  acidosis  there  are  marked 
signs  of  intestinal  irritation,  and  vomiting  is  often  a  prominent  symp- 
tom. But  these  facts  furnish  no  ground  for  the  assumption  that  the 
acetone  bodies  were  formed  in  the  alimentary  tract;  the  correct 
interpretation  must  regard  the  vomiting  as  a  symptom  of  an  internal 
auto-intoxication,  just  as  may  be  seen,  for  example,  in  uremia. 

The  native  proteins  are  resistant  to  putrefaction  in  the  intestine. 
It  is  the  products  of  the  digestion  of  proteins,  the  amino-acids,  and 
the  products  of  the  digestion  of  the  alimentary  secretions,  also  amino- 
acids,  of  course,  that  constitute  the  main  substrate  for  bacterial  action. 
This  occurs  to  some  extent  in  the  entire  intestinal  tract,  it  is,  however, 
more  marked  as  the  contents  descend  the  tract,  being  most  pronounced 
in  the  colon.  The  chief  interest  in  the  processes  of  putrefaction  centres 
in  the  derivatives  of  tyrosin,  phenyl-alanin,  tryptophan,  and  histidin. 

Putrefaction  of  Tyrosin  and  Phenylalanin. — The  putrefaction  of  these 
two  phenyl-amino-acids  follows  a  course  very  different  from  the  tissue 
catabolism  of  these  two  substances.  In  the  processes  of  putrefaction 
the  tendency  is  to  retain  the  aromatic  ring  and  to  build  down  the  fatty 
acid  following  deaminization;  thereupon  the  aromatic  derivative  is 
usually  conjugated.  In  the  catabolism  in  the  tissues,  the  aromatic 
ring  is  ruptured,  and  the  entire  molecule  burned.    It  may  perhaps  be 


PRODUCTS  OF  BACTERIAL  ACTION  ON  FOODSTUFFS       219 

going  too  far  to  state  that  none  of  the  aromatic  derivatives  of  protein 
catabolism  appear  in  the  urine;  it  will  be  pointed  out  that  possibly  a 
trace  of  benzoic  acid  is  thus  derived.  But  for  practical  purposes,  all 
the  aromatic  bodies  of  the  urine  are  derived  from  the  bacterial  decom- 
position of  the  aromatic  amino-acids  in  the  intestine.  Tyrosin  is  first 
deaminated,  then  the  resulting  p-oxy-phenyl-propionic  acid  is  oxidized 
to  p-oxy-phenyl-acetic  acid;  this  is  then  reduced  to  phenol  or  cresol. 

Tyrosin      p-oxyphenyl-propionic  acid       p-oxy-phenyl-acetic  acid      Para-cresol  Phenol 

C.OH  C.OH  C.OH  C.OH  C.OH 


HC      CH  HC      CH  HC      CH  HC      CH  HC      CH 

II  -II-  II-  11-11 

HC      CH  HC      CH  HC      CH  HC      CH  HC      CH 


V  V  v  v  \/ 

C.CH2  C.CHo  C.CH2  C.CH3  CH 

CHNH2  CH2  COOH 

COOH  COOH 

Some  of  the  phenol  is  oxidized  to  hydrochinon,  a  part  to  orthodioxy- 
benzene.  These  all  are  eliminated  in  part  as  simple  salts,  in  larger 
part  conjugated  with  sulphuric  acid  as  the  aromatic  or  ethereal  sulphates, 
and  in  traces  uncombined.  The  conjugations  do  not  occur  in  the  intes- 
tine; the  substances  are  absorbed  directly  and  the  conjugation  occurs  in 
the  liver.  If  the  amounts  be  large  or  the  available  sulphuric  acid  be 
scanty,  conjugation  will  occur  with  d-glucuronic  acid,  beyond  the 
small  fraction  always  thus  combined.  It  is  possible  that  a  fraction 
of  the  tyrosin  or  phenylalanin  is  converted  into  benzoic  acid,  and  that 
the  trace  of  hippuric  acid  present  in  the  urine  of  a  subject  on  a  meat 
diet  may  have  been  thus  derived. 

The  putrefaction  of  phenylalanin  is  not  well  understood.  In  the 
horse  phenylalanin  is  converted  first  into  phenylpropionic  acid,  in  a 
manner  analogous  to  the  building  down  of  tyrosin,  then  into  phenyl- 
acetic  acid,  which  is  eliminated  bound  with  glycocoll  as  phenaceturic 
acid.  But  this  last-named  substance  is  not  found  in  human  urine. 
It  has  been  suggested  that  the  phenylalanin  might  be  converted  into 
benzoic  acid,  but  this  is  unlikely  in  any  quantity.  However  accom- 
plished, it  is  certain  that  it  is  putrefied  to  paracresol  or  phenol,  just 
as  is  tyrosin.  As  stated,  a  small  fraction  of  these  aromatic  bodies  is 
eliminated  in  the  urine  free,  a  variable  amount  as  simple  salts,  the 
larger  amount  normally  conjugated  with  sulphuric  acid.  It  must, 
however,  not  be  assumed  that  all  the  aromatic  bodies  resorbed  from 
the  intestine  reappear  in  the  urine;  quite  the  contrary,  a  certain  unde- 
termined fraction  is  burned.  This  is  made  certain  by  the  familiar 
observation  that  if  a  dose  of  phenol  be  ingested,  it  can  never  be  recovered 
quantitatively  in  the  urine,  and  it  is  believed  that  the  missing  fraction 
is  burned.  Phenol  and  cresol  are  never  in  the  body  converted  into  indol 
or  skatol.     Outside  of  the  body  histidin  yields  imidazolethylamin. 


220 


DIGESTION 


Tryptophan. — The  parent  substance  of  indol  and  skatol  is  trypto- 
phan. Tryptophan  is  indol- a-amino-propionic  acid.  This  is  deami- 
nated,  the  propionic  acid  oxidized  to  acetic  acid,  this  then  splits  off 
or  is  burned,  and  the  indol  oxidized  to  indoxyl,  the  later  reactions 
occurring  in  the  tissues  after  resorption  from  the  intestine. 


Tryptophan 

CH 


HC       C C — CH2 

II        II        I 
HC       C      CH    CHNH2 

COOH 


CH   NH 


Indol-acetic  acid 

CH 


HC       C C CH2 

HC       C      CH  COOH 

VV 
CH    NH 


Indol-propionic  acid 

CH 


HC 

I 
HC 


C — C 

I        II 

c 


CH2 

II        I 
CH  CH2 


CH    NH     COOH 


i 


Indol 

CH 

HC       C — CH 

I        I        II 
HC       C      CH 

VV 

CH    NH 


Indoxy 

CH 
HC       CH— COH 


HC       CH    CH 

\/ 
NH 


YhX 


The  indoxyl  is  conjugated  with  sulphuric  acid,  sometimes  with  d-glu- 
curonic  acid.  The  indol-acetic  acid  is  probably  the  urorosein  of  the 
urine.  From  indol-acetic  acid,  by  splitting  off  CO2,  methylindol  or 
skatol  is  derived. 


Indol-acetic  acid 

CH 


HC       C — C CH2 

I         I        II        I 
HC       C      CH  COOH 

VV 
CH     NH 


Skatol 

CH 
HC       C — C— 
HC       C      CH 

V  V 

CH    NH 


-CH3 


+     co2 


So  far  as  known  indol  or  its  related  substances  are  never  converted 
in  the  body  into  phenol.  The  two  series  are  entirely  independent. 
It  is  possible  that  tryptophan  in  the  intestinal  tract  has  also  another 
source.  According  to  present  conceptions  hematin,  the  non-protein 
component  of  hemaglobin,  is  a  tetrapyrrol,  linked  by  iron. 


— C— C 


c— c- 


L>\  /-U- 


\     / 

X 

-c— c      /    \      c— c— 


i 


/ 


\ 


X 


N< 


c— c— 


A  glance  at  the  constitution  of  tryptophan  suggests  that  this  body  may 
be  formed  by  the  combination  of  one  of  the  pyrrol  groups  with  a  benzene 


PRODUCTS  OF  BACTERIAL  ACTION  ON  FOODSTUFFS       221 

ring.  The  point  is  of  interest,  for  it  may  indicate  the  synthesis  of  the 
indol  ring  in  plants.  For  us  here  the  suggestion  has  a  different  meaning; 
if  this  be  the  constitution  of  hematin,  might  we  expect  to  find  trypto- 
phan (or  prolin)  in  the  bile  or  intestine  as  the  result  of  its  catabolism? 
This  is  not  the  only  direction  in  which  bacteria  decompose  tyrosin, 
phenylalanin,  and  tryptophan.  The  tyrosin  and  phenylalanin  may  be 
converted  into  amins  instead  of  being  deaminated,  C02  being  split  off. 


Tyrosin 

COH 

/\ 
HC       CH 

I 
CH 


Hi 


C.CH2 

CHNH2 

I 

COOH 


Oxyphenylethylamin 

COH 


HC       CH 
HC       CH 

v 

C.CH2 

CH2NH2 
C02 


Phenylalanin 

CH 
HC       CH 
HC       CH 

v 

C.CH2 

I 


CHNH2 

I 

COOH 


Phenylethylamin 

CH 
HC       CH 


Hi 


tf 


CH2 

I 
CH2NH2 

C02 


These  are  not  regular  constituents  of  the  urine,  but  appear  usually  in 
the  decomposition  of  protein. 

The  amount  of  sulphuric  acid  combined  with  these  aromatic  bodies 
varies  from  0.1  to  0.7  gram  per  day,  a  striking  enough  variation.  It 
is  not  possible  with  any  degree  of  accuracy  to  estimate  these  bodies 
directly,  we  can  only  measure  the  acid  with  which  they  are  conjugated. 
Current  in  the  medical  literature  during  the  last  twenty  years  are 
four  erroneous  statements  bearing  upon  this  subject.  Diagnosis, 
physiology,  and  pharmacology  have  been  erected  on  these  four  propo- 
sitions, not  one  of  which  is  sound.    These  are  as  follows: 

(a)  The  aromatic  bodies  combined  with  sulphuric  acid  in  the  urine 
are  the  only  aromatic  bodies  in  the  urine,  and  the  estimation  of  the 
ethereal  sulphates  may  be  used  to  measure  the  total  aromatic  bodies 
in  the  urine. 

(6)  The  conjugated  sulphates  of  the  urine  represent  the  quantity  of 
aromatic  bodies  formed  by  bacteria  in  the  intestine. 

(c)  The  quantity  of  indoxyl  is  representative  of  the  aromatic  bodies 
of  the  intestine,  and  of  the  quantity  of  aromatic  bodies  formed  in  the 
intestine  by  bacteria. 

(d)  The  aromatic  bodies  of  the  urine  are  representative  of  the 
intensity  of  bacterial  processes  in  the  intestine. 

It  is  easy  to  demonstrate  that  each  one  of  these  propositions  is 
unfounded;  but  more,  each  may  be  shown  to  be  untrue. 

(a)  The  urine  contains  (apart  from  hippuric  acid  which  is  not  here 
concerned)  aromatic  bodies  not  conjugated  with  sulphuric  acid.  For 
example,  both  p-oxy-phenyl  propionic  and  p-oxy-phenyl  acetic  acid 
are  present  as  simple  salts  in  the  urine,  in  notable  but  undetermined 
amounts.  Furthermore,  waving  aside  the  possibility  of  free  volatile 
aromatic  bodies  being  present,  for  which  there  is  some  evidence,  aro- 


222  DIGESTION 

matic  bodies  are  always  present  in  conjugation  with  d-glucuronic  acid. 
The  methods  for  the  estimation  of  the  aromatic  bodies  that  exist  in 
the  urine  apart  from  the  ethereal  sulphates  are  so  difficult  and  so  unre- 
liable, that  we  are  not  in  a  position  to  state  how  large  the  fraction  is. 
One  sees,  however,  urines  of  vegetarians  on  a  low  protein  input,  in 
which  it  is  certain  that  a  large  fraction,  possibly  the  larger  fraction,  of 
the  aromatic  bodies  in  the  urine  exists  outside  of  the  ethereal  sulphates. 

(6)  The  conjugated  sulphates  are  not  representative  of  the  quantity 
of  aromatic  bodies  formed  in  the  intestine,  unless  all  exogenous  aromatic 
bodies  are  excluded.  This,  however,  can  be  done  only  on  a  meat  diet, 
as  all  fruits  and  vegetables  contain  aromatic  bodies,  that  in  part  pass 
into  phenols  or  cresols,  in  part  into  benzoic  acid.  It  is  a  matter  of 
experience  that  the  ethereal  sulphates  of  the  urine  rise  when  a  subject 
is  taken  from  a  meat-fat-starch  diet  and  placed  upon  a  vegetable  diet. 
It  is  possible,  of  course,  that  the  reactions  of  putrefaction  of  protein 
are  increased  with  a  vegetable  diet;  certain  vegetable  proteins  in  par- 
ticular (as  the  legumens)  seem  very  prone  to  putrefaction.  But  on 
the  other  hand,  it  is  certain  that  phenol-bearing  bodies  in  fruits  and 
vegetables  augment  the  phenols  of  the  urine.  It  is  clear,  therefore, 
that  if  one  wishes  to  use  the  ethereal  sulphates  (or  total  urinary  aromatic 
bodies)  of  the  urine  as  an  index  of  the  bacterial  formation  of  phenols 
in  the  intestine,  the  exogenous  phenols  would  at  least  have  to  be  excluded 
from  the  diet — something  that  the  proponents  of  the  proposition  have 
not  done. 

Furthermore,  if  the  aromatic  bodies  of  the  urine  are  to  be  regarded 
as  an  index  of  the  aromatic  bodies  of  the  intestine  in  a  quantitative 
way,  it  will  need  to  be  established  that  none  of  these  aromatic  bodies 
that  are  resorbed  from  the  intestine  are  destroyed  in  the  body.  Now 
it  is  certain  that  resorbed  aromatic  bodies  of  the  intestine  are  to  some 
extent  destroyed  in  the  body.  The  degree  of  destruction  is  not  known 
and  is  not  now  measurable.  It  is  possible  that  the  variations  in  urinary 
aromatic  bodies  in  different  individuals  might  be  due  to  differences  in 
the  powers  of  combustion  of  aromatic  bodies,  and  we  have  no  way  of 
excluding  this.  The  fact  that  the  partition  of  the  aromatic  bodies  is 
known  to  vary  from  individual  to  individual  supports  this  possibility. 

More  important  still  is  the  tacit  assumption  that  either  all  the  aro- 
matic bodies  formed  in  the  urine  are  resorbed  or  that  the  degree  of 
resorption  is  more  or  less  constant,  from  time  to  time  in  the  same  subject 
and  also  in  different  individuals.  Now  this  is  unfounded.  Often  the 
resorption  of  the  aromatic  bodies  from  the  intestine,  especially  in  con- 
nection with  a  simple  meat  and  starch  diet,  is  nearly  complete;  the 
stools  yield  little.  But  on  the  other  hand,  it  is  common  to  find  a  stool, 
in  the  entire  absence  of  diarrhea,  that  gives  an  intense  reaction  for 
aromatic  bodies.  One  sees  formed  stools  that  contain  more  aromatic 
bodies  than  does  the  urine.  As  a  rule,  constipation  affords  greater 
opportunity  for  resorption,  while  diarrhea  lessens  resorption.  In  main 
diseases  with  loose  and  frequent  stools,  the  feces  are  heavily  charged 


PRODUCTS  OF  BACTERIAL  ACTION  ON  FOODSTUFFS       223 

with  aromatic  bodies,  while  the  urine  is  nearly  free.  It  is  entirely 
possible  that  apart  from  the  question  of  diarrhea,  variations  in  resorp- 
tion may  occur,  due  to  conditions  in  the  mucosa.  This  is  suggested 
by  the  facts  in  starvation.  In  starvation  the  bacteria  form  large 
amounts  of  aromatic  bodies  from  the  proteins  of  the  alimentary  secre- 
tions. It  is  usual  to  find  a  moderate  reaction  for  aromatic  bodies  in 
the  urine  and  a  heavy  reaction  in  the  stools,  and  this  even  though  the 
stool  be  passed  daily.  Now  with  all  the  possible  variations  in  the  degree 
of  resorption  of  aromatic  bodies  from  the  intestine  (to  say  nothing  of 
the  differences  in  the  amounts  actually  formed  there)  how  can  the 
quantity  in  the  urine,  even  if  completely  and  properly  estimated,  be 
taken  as  an  index  of  the  amount  formed  in  the  intestine? 

(c)  Today,  when  the  direct  source  of  indoxyl  is  definitely  under- 
stood, to  regard  the  quantity  of  indican  in  the  urine  as  an  index  of  the 
total  aromatic  bodies  formed  in  the  intestine,  either  by  bacteria  or  in 
any  way  there  derived,  is  nothing  less  than  an  egregious  blunder. 
Indoxyl  is  derived  from  tryptophan ;  the  phenols  are  derived  from  tyrosin 
and  phenylalanin;  these  are  independent  processes,  and  the  products 
depend  upon  the  substrate  concentrations.  If  a  diet  be  poor  in  trypto- 
phan, the  stools  and  the  urine  must  be  poor  in  indoxyl,  it  makes  no 
difference  how  much  phenol  derivatives  it  contains.  If  a  diet  be  rich 
in  tyrosin  and  phenylalanin,  the  feces  and  urine  may  be  rich  in  the 
different  phenol  derivatives,  it  makes  no  difference  how  much  indoxyl 
is  present.  The  presence  of  indoxyl  is  a  reaction  only  for  the  putre- 
faction of  tryptophan.  If  the  proteins  of  the  diet  be  poor  in  trypto- 
phan, it  makes  no  difference  how  many  or  what  bacteria  are  in  the 
intestine,  they  cannot  form  indoxyl  from  the  products  of  digestion. 
If  an  individual  be  given  a  diet  containing  fat  and  starch  with  25  grams 
of  egg  albumin  and  the  same  amount  of  gelatin,  the  reaction  for  indoxyl 
in  the  urine  becomes  very  faint.  Gelatin  is  devoid  of  tryptophan, 
egg  albumin  is  not  rich  in  it.  It  is  not  possible,  however,  to  exclude 
tryptophan  from  the  alimentary  tract.  A  diet  free  of  tryptophan 
will  not  support  nitrogenous  balance,  as  the  tryptophan  is  absolutely 
essential  to  the  anabolism  of  protein.  This  deprivation,  however, 
the  body  could  tolerate  for  the  purposes  of  a  test.  But  the  test  could 
not  be  relied  upon  because  the  intestinal  mucin  contains  tryptophan 
and  the  indoxyl  reaction  persists  during  starvation,  being  then  less 
prominent  in  the  urine,  but  intense  in  the  feces. 

With  a  fixed  diet,  constant  in  tryptophan,  would  it  be  possible  to 
assume  that  the  indoxyl  of  the  urine  is  an  approximate  index  of  the 
putrefaction  of  tryptophan  in  the  intestine?  Only  if  all  the  indol 
were  resorbed  or  if  the  degree  of  resorption  were  constant.  These 
conditions  cannot,  however,  be  experimentally  attained.  A  strong 
indoxyl  reaction  in  the  urine  might  be  due  to  a  good  resorption  and 
a  faint  reaction  to  a  poor  resorption,  the  intestinal  content  of  indol 
being  the  same  in  the  two  cases.  Nor  are  diarrhea  or  constipation 
required  to  insure  respectively  low  and  high  resorption.     The  color 


224  DIGESTION 

reactions  of  indoxyl  are  so  pronounced  and  the  amount  required  to 
give  a  test  so  minimal,  it  is  clear  that  variations  that  could  have  no 
other  than  an  incidental  meaning  might  lead  to  striking  differences 
in  the  color  tests  in  the  urine.  It  is,  therefore,  certain  that  the  reac- 
tion for  indican  is  much  less  qualified  to  be  used  as  an  index  of  the 
aromatic  bodies  in  the  intestine  than  is  the  estimation  of  the  total 
ethereal  sulphates,  in  which  the  indican  is  largely  included.  Indicanemia 
as  a  sign  of  uremia,  as  recently  suggested,  has  not  been  established, 
though  this  present  verdict  is  still  insecure  on  account  of  difficulties 
in  the  methods  of  analysis.  If  proved,  it  would  amount  to  a  specific 
uremic  threshold  value  for  indican,  though  in  nowise  suggesting  the 
substance  as  the  toxic  agent  in  the  condition. 

(d)  It  may  be  true,  but  need  not  be  true,  that  the  total  aromatic 
bodies  of  the  urine  are  an  index  of  the  intensity  of  bacterial  processes 
in  the  intestine.  There  are  three  factors  that  may  modify  the  results: 
the  factor  of  resorption,  the  flora  of  the  intestine,  and  the  nature  of  the 
diet.  The  factor  of  resorption,  and  the  marked  variations  to  which 
it  is  subject,  has  been  discussed  and  needs  no  further  reference.  But  it 
is  clear  that  in  the  sense  in  which  proposition  (d)  is  made,  the  total 
amount  of  aromatic  bodies  formed  in  the  intestine  (fecal  plus  urinary 
aromatic  bodies)  cannot  be  assumed  to  be  an  index  of  the  intensity 
of  the  bacterial  processes  in  the  intestine.  At  the  most,  the  total 
production  of  aromatic  bodies  must  depend  on  the  nature  of  the  diet, 
and  on  the  flora  of  the  intestine.  There  are  saprophytes  that  are 
active  in  the  formation  of  aromatic  bodies;  there  are  pathogenic  germs, 
like  the  cholera  bacillus,  that  are  active.  There  are  saprophytes  like 
the  bacillus  of  lactic-acid  fermentation,  that  are  not  active  in  the 
formation  of  aromatic  bodies;  there  are  disease-producing  germs,  like 
the  typhoid  bacillus,  that  are  but  slightly  active.  It  is,  therefore,  not 
only  a  question  of  the  intensity  of  the  bacterial  processes  of  the  intes- 
tine, it  is  a  question  also  of  the  flora.  One  flora  may  be  very  active, 
but  not  operate  especially  in  this  direction.  Another  flora  may  be 
inactive,  but  may  operate  especially  in  this  direction.  Thus  in  some 
of  the  gastro-enteric  diseases  of  children,  the  aromatic  bodies  are  present 
in  the  urine  and  stools  in  very  small  amounts,  even  without  diarrhea. 
In  starvation,  on  the  other  hand,  the  intensity  of  the  bacterial  processes 
in  the  intestine  cannot  be  regarded  as  abnormal,  but  there  will  be  a 
goodly  production  of  aromatic  bodies  from  the  intestinal  mucin. 

Not  only  is  the  flora  of  importance,  the  type  of  proteins  in  the  diet 
must  be  of  some  importance.  As  a  rule,  the  plant  proteins  are  some- 
what richer  in  tyrosin  and  phenylalanin  than  the  animal  proteins  that 
are  used  as  food.  All  circumstances  of  resorption  and  flora  regarded 
as  fixed,  it  seems  clear  that  more  aromatic  bodies  are  formed  on  a  mixed 
diet  than  on  a  meat  and  starch  diet,  though  the  occurrence  of  preformed 
phenols  in  plants  leads  one  to  make  the  statement  less  equivocal  than 
the  figures  would  indicate.  In  actual  life,  the  factors  of  resorption  and 
intestinal  flora  may  be  regarded  as  of  much  greater  importance  than 
the  question  of  the  aromatic  content  of  the  proteins  of  the  diet. 


PRODUCTS  OF  BACTERIAL  ACTION  ON  FOODSTUFFS       225 

In  times  gone  by,  it  was  usual  to  draw  conclusions  from  the  ratio 
of  ethereal  sulphates  to  total  sulphates.  These  two  magnitudes  are 
now  recognized  to  represent  different  variables,  and  the  ratio  has  no 
meaning  that  bears  on  the  interpretation  of  the  ethereal  sulphates  as 
an  index  of  intestinal  processes.  The  estimation  of  the  total  ethereal 
sulphates  remains  the  sole  method  upon  which  any  conclusion  as  to 
the  formation  of  aromatic  bodies  in  the  intestine  may  be  based.  But 
such  conclusion,  for  the  reasons  and  facts  above  stated,  is  very  likely 
to  be  incorrect;  so  liable  to  be  wrong  in  fact  as  to  make  this  estimation 
an  unreliable  guide  for  diagnosis  or  treatment. 

The  conjugation  of  the  aromatic  bodies  with  sulphuric  and  glucuronic 
acids  in  the  liver  is  in  a  certain  sense  an  act  of  distoxication.  The 
phenols  are  quite  innocuous  when  conjugated  with  sulphuric  acid. 
This  state  of  conjugation  is  in  nowise  peculiar  to  the  phenols,  many 
substances  are  thus  distoxicated,  for  example,  orcin,  thymol,  pyrogallol, 
and  resorcin.  The  reaction  occurs  in  the  liver,  and  the  sulphuric  acid 
is  withdrawn  from  the  common  sulphate  derived  from  the  oxidation 
of  cystin.  The  normal  catabolism  of  protein  yields  more  sulphuric 
acid  than  is  required  for  conjugation  with  aromatic  bodies  formed  in 
the  intestinal  tract.  That  traces  of  glucuronic  acid  exist  in  normal 
urine  combined  with  aromatic  bodies  is  not  the  result  of  lack  of  sul- 
phuric acid;  it  is  to  be  regarded  as  a  partition.  The  conjugation  in 
the  liver  is  probably  a  purely  chemical  reaction,  requiring  no  action 
on  the  part  of  the  liver  cells  and  constituting,  therefore,  no  task  in  the 
metabolic  sense.  In  this  respect  it  resembles  the  combination  of  the 
ketonic  acids  with  ammonia,  although  the  reactions  are  not  exactly 
of  the  same  order.  In  any  event,  there  can  be  no  idea  that  the  conjuga- 
tion of  the  aromatic  bodies  in  the  liver  is  a  burden  to  the  liver  that 
one  should  attempt  to  minimize  as  much  as  possible  by  restriction  of 
the  formation  of  the  aromatic  substances  in  the  intestine.  There  is, 
furthermore,  no  foundation  for  the  idea  that  the  elimination  of  these 
bodies  constitutes  a  burden  to  the  kidneys,  since  in  the  conjugated 
state  the  aromatic  bodies  are  practically  non-irritating. 

Normal  urine  contains  traces  of  a  base,  methyl-pyridyl-ammonium. 

CH 


HC       CH 


1     in 


N 

/\ 

H3C       OH 

This  must  in  some  way  be  derived  from  the  benzene  nucleus  of  one 
of  the  aromatic  amino-acids,  probably  by  bacterial  action  within  the 
intestine,  rather  than  in  the  catabolism  of  protein — unless  indeed  it  is 
derived  from  coffee,  tea,  or  tobacco. 

Hippuric  Acid. — Hippuric  acid  is  a  combination  of  benzoic  acid 
and  glycocoll.    The  reaction  is  as  follows; 
15 


22G 


DIGESTION 


Benzoic  acid  +  glycocoll  =  hippuric  acid  +  water 


HC 


CH 

/XCH 


Y, 


CH 
COOH 


CH2NH2 
COOH 


CH 
HC       CH 
HC       CH 

Yco 

I 

CH2NH 
COOH 


+    H20 


This  is  again  a  reaction  of  distoxication.  The  benzoic  acid  withdraws 
glycocoll  from  the  urea  metabolism,  quite  as  the  ketonic  acids  with- 
draw ammonia  from  the  urea  metabolism.  This  reaction  is  an  illustra- 
tion of  a  common  type  in  the  pharmacological  field,  many  other  sub- 
stances being  thus  distoxicated  by  combination,  among  them  salicylic 
acid,  toluylic  acid,  phenyl-acetic  acid,  nitrobenzoic  acid,  thiophen 
aldehyd,  cinnamic  and  quinic  acids. 

There  are  apparently  four  sources  for  the  benzoic  acid  that  is  re- 
covered from  the  urine  as  hippuric  acid,  (a)  From  the  aromatic  amino- 
acids  of  the  digested  proteins  of  the  alimentary  tract.  (6)  Preformed 
benzoic  acid  in  fruits  and  vegetables,  (c)  Benzoic  acid  formed  from 
aromatic  compounds  of  various  kinds,  present  in  fruits  and  vegetables 
and  set  free  by  hydrolysis  in  the  alimentary  tract,  (d)  Benzoic  acid 
formed  from  aromatic  bodies  in  fruits  and  vegetables  by  bacterial  action 
within  the  alimentary  tract. 

Traces  of  hippuric  acid,  up  to  C.l  gram  per  day,  are  to  be  found  in 
the  urine  in  starvation,  on  milk  diet  and  on  meat  diet.  The  sole  source 
of  this  benzoic  acid  must  be  the  phenyl-amino-acids,  either  within 
the  alimentary  tract  or  in  the  protein  catabolism.  It  seems  quite 
certain  that  the  former  is  the  single  source.  When  phenyl-propionic 
acid  is  introduced  into  animals,  it  is  oxidized  to  benzoic  acid  in  part; 
in  part  it  remains  as  phenyl-acetic  acid.  The  phenyl-propionic  acid 
would  be  most  naturally  derived  from  phenylalanin. 


Phenylalanin 

Phenylpropionic  acid 

Phenylacetic  acid 

Benzoic  acid 

CH 
HC       CH 
HC       CH        -> 

C.CHj 

1 

CH 
HC       CH 
HC       CH       -♦ 
C.CH2 
CH2 
COOH 

CH 

HC       CH 

i         i 

CH 
HC       CH 
HC       CH 

C.COOH 

HC       CH       -* 

v 

C.CH2 
COOH 

CHNH2 
COOH 

From  the  phenyl-acetic  acid  phenol  is  also  formed  by  bacteria. 

It  is  possible  that  tyrosin  might  also  be  converted  into  benzoic  acid, 
although  it  is  a  little  difficult  to  understand  how  the  tyrosin  is  to  be 
reduced  to  phenylalanine 


PRODUCTS  OF  BACTERIAL  ACTION  ON  FOODSTUFFS       227 

On  mixed  diets  the  hippuric  output  varies  from  0.3  to  1  gram  per 
day.  The  urine  of  vegetarians  and  fruitarians  may  contain  up  to  or 
over  2  grams  per  day.  Hippuric  acid  in  the  urine  is  characteristic  of  the 
herbivorous  diet.  In  man  the  largest  portion  of  the  hippuric  acid 
is  formed  from  benzoic  acid  derived  from  the  components  of  the  diet 
under  fractions  b,  c,  and  d.  Many  fruits,  like  cranberries,  contain 
large  amounts  of  benzoic  acid,  and  all  fruits  and  vegetables  contain 
goodly  amounts  of  different  compounds  that  on  hydrolysis  or  oxida- 
tion yield  benzoic  acid. 

The  site  of  the  conjugation  of  benzoic  acid  and  glycocoll  to  hippuric 
acid  is  the  kidney.  By  this  we  do  not  mean  that  in  the  nephrectomized 
animal  hippuric  acid  cannot  be  formed.  But  for  practical  purposes 
the  reaction  is  held  to  occur  in  the  kidney.  The  conjugation  is  a  fer- 
ment reaction,  and  is  accomplished  under  favorable  conditions  by  fresh 
kidney  pulp  and  in  the  perfused  kidney. 

Benzoic  acid  is  also  conjugated  with  d-glucuronic  acid  and  a  trace 
of  this  compound  is  believed  to  be  present  in  normal  urine. 

The  amount  of  glycocoll  available  in  the  normal  protein  catabolism 
is  far  more  than  sufficient  to  combine  with  any  amount  of  benzoic  acid 
that  may  be  ingested  in  the  natural  state  in  foods.  When  benzoic 
acid  is  ingested  directly  it  is  found  that  glycocoll  is  available  in  amounts 
far  in  excess  of  the  quantity  of  glycocoll  to  be  derived  from  the  day's 
catabolized  protein.  This  glycocoll  must  be  synthesized  in  the  body 
or  else  derived  from  the  body  protein.  Experimental  investigations 
have  indicated  that  the  latter  course  is  the  method  adopted  to  secure 
the  glycocoll.  The  body  builds  down  protein  from  its  tissues  and  thus 
secures  glycocoll.  When  large  doses  of  benzoic  acid  are  administered 
to  an  animal,  there  will  be  an  excess  of  nitrogen  in  the  urine;  this  corre- 
sponds to  the  superfluous  fraction  of  the  molecule  of  protein  catabolized 
to  secure  the  glycocoll.  This  increase  in  nitrogen,  curiously  enough,  is 
not  in  the  state  of  urea  but  is  included  in  the  rest  nitrogen,  and  prob- 
ably is  in  the  form  of  a  polypeptid  body  like  the  oxy-proteinic  acid. 
It  is  likely  from  this  that  the  catabolism  of  protein  under  these  circum- 
stances is  different  from  the  normal.  Whether  the  glycocoll  is  secured 
merely  in  proportion  to  its  occurrence  in  the  protein  catabolized,  or 
whether  it  is  also  formed  from  other  amino-acids  is  not  known.  The  body 
proteins  drawn  upon  are  supposedly  the  proteins  of  the  connective- 
tissue  group,  some  of  which  are  very  rich  in  glycocoll. 

Whether  the  conjugation  of  benzoic  acid  with  glycocoll  is  to  be 
regarded  as  a  burden  to  the  kidneys  is  difficult  of  determination.  The 
kidney  in  nephritis  is  sometimes  defective  in  this  function;  but  it  has 
not  been  shown  that  the  elimination  of  the  hippuric  acids  is,  like  sodium 
chlorid  in  excess,  a  burden  to  the  organ.  The  carnivorous  diet  is 
commonly  regarded  as  being  most  onorous  to  the  kidneys,  while  the 
largest  amounts  of  hippuric  acid  are  to  be  found  in  the  urine  of 
vegetarians  and  fruitarians. 


APTEK    IV 

METABOLISM 
GENERAL   CONSIDERATIONS    OF   METABOLISM 

Under  the  term  metabolism  we  understand  the  series  of  chemical 
processes  through  which  the  foodstuffs  are  carried  (a)  in  the  conserva- 
tion of  the  tissues  of  the  body  and  (b)  in  the  maintenance  of  body 
temperature  and  of  physical  work.  The  upkeep  of  a  machine  com- 
prises the  replacement  of  worn  parts,  lubrication,  and  fuel.  The  upkeep 
of  the  body  comprises  the  replacement  of  worn  parts  and  fuel.  What 
do  we  mean  by  the  replacement  of  worn  parts?  Cells  have  a  limited 
life,  and  the  status  quo  must  be  maintained  by  the  regeneration  of 
new  cells  to  replace  those  that  die.  These  new  cells  are  formed  from 
the  foodstuffs;  not  normally  from  the  materials  of  the  dead  cells.  This 
is  a  point  of  fundamental  importance.  When  a  cell  dies,  its  material  is 
disintegrated  and  cast  out;  it  has  normally  no  further  utilization  in 
the  body.  The  new  cell,  formed  by  process  of  reproduction  from  a 
preexisting  cell  of  its  type,  is  maintained  in  its  growth  by  new  material 
derived  from  the  foodstuffs.  In  the  case  of  a  machine,  the  worn  parts 
may  be  recast  into  new  parts;  in  the  case  of  an  animal  organism,  the 
worn  parts  are  normally  discarded.  All  cell  formations  during  normal 
life  are,  therefore,  maintained  through  the  utilization  of  new  raw 
material,  from  the  daily  food  in  large  part,  in  small  part  from  stored 
food  if  need  be.  For  the  most  part,  however,  the  formation  of  new 
cells  is  dependent  upon  daily  food.  As  will  be  later  described,  in  starva- 
tion the  body  may  exercise  a  faculty  of  adaptation  in  this  respect, 
in  that  the  formation  of  the  important  cells  of  the  body  is  maintained 
at  the  expense  of  the  degeneration  of  less  important  cells,  i.e.,  the 
nervous  system  and  glands  are  maintained  at  the  expense  of  connective 
tissue  and  skeletal  muscles.  With  the  maintenance  of  cellular  regenera- 
tion in  adult  life  is  to  be  classed  the  maintenance  of  growth  in  the 
young.  It  means,  however,  more  than  this.  Living  cells  must  suffer 
wear  and  tear  in  the  course  of  chemical  functionation.  The  relative 
values  of  these  two  fractions  of  regeneration  of  new  cells  and  wear 
and  tear  of  functionating  cells  vary  with  different  tissues.  Together  the 
two  comprise  the  total  upkeep  of  the  cells.  Body  heat  and  body  work 
may  be  classed  together.  For  these  the  foodstuffs  act  as  fuel.  The 
upkeep  of  the  body  means  then  the  maintenance  of  the  working  parts 
and  the  supply  of  fuel. 

These  two  phases  of  metabolism  are  shared  by  each  of  the  three 
main  foodstuffs — the  proteins,  the  carbohydrates,  and  the  fats.     In 


GENERAL  CONSIDERATIONS  OF  METABOLISM  229 

the  quantitative  sense,  it  is  true  the  proteins  have  the  more  important 
share  in  the  upkeep  of  the  tissues,  and  the  fats  and  sugar  the  most 
important  share  in  the  production  of  heat  and  support  of  work.  But 
heat  is  always  evolved  in  the  protein  catabolism  and  the  entire  fuel 
needs  of  the  body  can  be  maintained  by  the  combustion  of  protein. 
On  the  other  hand,  lipoids  and  sugars  are  indispensable  constituents 
of  protoplasm. 

In  miniature,  both  in  time  and  space,  the  processes  of  the  growth 
and  maintenance  of  tissues  are  illustrated  in  the  hatching  of  the  chick. 
The  egg  contains  fat,  a  little  carbohydrate,  and  much  protein.  On 
account  of  lack  of  oxygen,  there  is  no  heat  metabolism  in  the  hatching 
chick,  the  heat  necessary  for  the  preservation  of  cell  life  must  be 
furnished  from  the  outside.  From  the  materials  in  the  egg,  all  the 
structures  of  the  chick,  all  the  cells  of  the  glands,  nervous  system, 
connective  tissues,  skeleton,  skin,  nails,  feathers,  digestive  tract,  etc., 
are  formed.  Once  the  anlage  is  established,  growth  and  upkeep  are 
identical  in  terms  of  metabolism,  the  difference  is  in  quantity.  Illus- 
trated in  the  hatching  of  the  chick  are  the  processes  of  upbuilding 
mostly,  and  but  few  of  disintegration,  on  account  of  the  lack  of  oxygen 
and  the  short  period  of  time  involved.  When  the  chick  is  hatched, 
the  heat  metabolism  is  added  to  the  tissue  metabolism,  and  the  pro- 
cesses of  dissimilation  are  inaugurated.  During  the  period  of  growth, 
the  building-up  processes  are  relatively  disproportionate  to  the  pro- 
cesses of  dismantlement;  during  mature  life  they  are  balanced;  with  the 
advance  of  age  the  disproportion  of  youth  is  reversed.  The  unit  of 
metabolism  per  unit  of  tissue  is  greatest  in  youth  and  least  in  old  age; 
this  applying  to  both  the  building-up  and  the  building-down  processes. 
The  building-up  processes  of  metabolism  we  term  anabolism;  the  build- 
ing-down process  we  term  catabolism.  In  the  series  of  processes  termed 
anabolism  the  foodstuffs  are  transformed  and  organized  into  the  cells 
and  tissues  of  the  body.  In  the  series  of  processes  termed  catabolism, 
worn  protoplasm  and  the  constituents  of  dead  cells  are  disintegrated 
and  cast  out  of  the  body.  And  side  by  side  with  these  processes  are 
the  reactions  of  combustion,  whereby  the  temperature  necessary  for  the 
life  of  the  cells  is  maintained  and  the  energy  needed  for  external  work 
furnished.    Life  represents,  therefore,  a  state  of  equilibrium. 

For  each  of  the  three  main  foodstuffs  we  may  divide  the  subject 
matter  as  follows: 

The  chemical  state  of  the  foodstuff  as  the  basis  of  utilization. 

The  state  in  which  it  exists  in  the  cells  and  other  tissues. 

The  chemical  processes  in  the  anabolic  transformations. 

The  chemical  processes  involved  in  the  disintegration  of  the  cells 
and  tissues. 

The  chemical  states  of  the  end  products  of  catabolism. 

The  elimination  of  the  end  products  of  catabolism  from  the  body. 

Schematically,  the  processes  of  metabolism  may  be  sketched  as 
follows : 


230 


METABOLISM 
Cells  and  tissues 


Foodstuff 


^' 


End  products 


Combustion 


This  scheme  applies  to  protein,  fat,  and  sugar,  with  quantitative  varia- 
tions only.  Because  not  yet  clearly  Understood,  the  anabolic  functions 
of  sugar  and  fat  have  been  long  neglected ;  modern  chemical  and  physio- 
chemical  investigations,  however,  have  taught  us  their  great  importance. 
The  lesser  importance  of  the  fuel  relations  of  protein  have  also  been 
realized  within  recent  years. 

A  subdivision  of  the  consideration  of  metabolism  into  chapters 
devoted  to  carbohydrates,  fats,  and  proteins  serves  well  if  we  devote 
a  separate  chapter  to  the  discussion  of  the  purin  metabolism,  that 
cannot  be  successfully  placed  under  either  protein  or  carbohydrate. 


CARBOHYDRATE   METABOLISM 

In  the  discussion  of  the  digestion  and  resorption  of  the  carbo- 
hydrates we  learned  that  the  end  product  of  these  processes  was  the 
aldohexose,  d-glucose.  This  is  the  form  of  sugar  delivered  to  the  blood 
of  the  portal  vein;  it  is  the  form  of  sugar  delivered  from  the  liver  to 
the  blood  of  the  hepatic  vein;  it  is  the  only  form  of  sugar  known  to 
exist  normally  in  the  blood  and  circulating  fluids.  There  are  other 
sugars  fixed  in  the  tissues;  these  must,  therefore,  be  derived  from 
d-glucose.  In  the  tissues  is  to  be  found  a  polysaccharid,  the  animal 
starch,  glycogen;  this  must  be  derived  from  d-glucose.  The  body 
forms  fat  from  d-glucose.  And  lastly,  the  body  burns  d-glucose  directly. 
The  metabolism  of  d-glucose  may  thus  be  represented  as  follows: 


sugars  of  tissues,  combined  and  free 
d-Glucose<f ly°0^  proximate  form  of  storage 
\^fat,  ultimate  form  of  storage 
fuel 


pentose 

galactose 

glucose 

glucosamin 

galatosamin 

chondroitin 


COMBINED   SUGARS    OF   THE   TISSUES 

That  a  moiety  of  carbohydrate  could  be  obtained  in  the  chemical 
disintegration  of  the  proteins  has  long  been  known.  Whether  this 
carbohydrate  was  an  admixture  or  present  in  combination;  and  if 


COMBINED  SUGARS  OF  THE  TISSUES  231 

combined,  whether  loosely  or  firmly  combined,  was  not  always  easy  of 
determination.  In  some  instances  glycogen  was  undoubtedly  involved. 
For  the  most  part,  however,  it  is  now  clear  that  we  have  to  deal  with 
special  forms  of  sugars.  The  demonstration  that  these  are  all  derived 
from  d-glucose  is  contained  in  the  fact  that  they  are  all  formed  on  a 
milk  diet,  the  sugar  of  which  is  in  digestion  converted  into  d-glucose. 
In  the  plant  world  sugars  exist  in  fixed  combinations  with  many  other 
substances,  and  of  these  the  glucosids  are  perhaps  best  known.  It  is 
possible  to  compare  the  fixed  combinations  of  sugar  in  the  animal  body 
with  the  glucosids  of  plants,  since  both  are  constituents  of  metabolism. 
The  Pentoses. — The  pentoses  are  sugars  containing  five  atoms  of 
carbon,  three  of  which  are  asymmetric,  and  possessing  the  common 
formula:  C5H10O5.  While  in  animals  they  exist  only  in  the  form  of 
the  sugars,  in  plants  they  exist  in  the  form  of  polysaccharids  termed 
pentosans,  related  to  pentoses  as  starch  is  related  to  dextrose.  So  far 
as  present  information  goes,  pentoses  exist  in  the  body  only  in  one 
localization,  chemical  and  morphological,  namely,  in  nucleic  acid,  in 
the  nuclei  of  cells.  No  pentose  is  to  be  found  in  the  blood,  in  the  cir- 
culating fluids,  in  protoplasm  or  in  connective  tissues  outside  of  the 
nuclei.  In  the  nucleic  acids  isolated  from  the  liver,  pancreas,  thymus, 
lymphatic  glands,  kidneys,  muscle,  and  brain,  one  form  of  pentose  has 
been  found,  d-ribose.  The  stereoisomeric  equations  of  d-ribrose,  d-  and 
1-arabinose,  and  d-glucose  are  reproduced  for  purposes  of  comparison. 

d-glucose  d-ribrose  d-arabinose  1-arabinose 

COH  COH  COH  COH 

HCOH  HCOH  HOCH  HCOH 

HOCH  HCOH  HCOH  HOCH 

HCOH  HCOH  HCOH  HOCH 

HCOH  CH2OH  CH2OH  CH2OH 


CH 


OH 


As  will  be  elucidated  later,  d-ribrose  is  combined  with  purins  and 
pyrimidins  to  form  ribosids,  which  with  phosphoric  acid  form  nucleo- 
ids that  in  simple  or  polymolecular  states  constitute  the  nucleic  acids 
of  the  nuclei  of  cells.  Thus  far  pentose  has  not  been  shown  to  exist 
in  the  body  in  any  other  combination.  The  pentose  of  the  glands  was 
formerly  supposed  to  be  1-xylose,  but  the  sugar  is  now  known  to  be 
d-ribrose.  The  amount  of  pentose  in  the  nuclei-rich  glands  is  quite 
large;  fresh  liver,  kidneys,  lymph  glands  and  thymus  contain  as  much 
as  a  half  of  1  per  cent.,  while  pancreas  contains  2  per  cent.;  brain  and 
muscle  contain  0.1  per  cent.  The  total  pentose  content  of  the  adult 
body  may  be  judged  at  20  grams.  Since  no  pentose  is  to  be  found  in 
the  blood,  it  would  follow  that  in  the  catabolism  of  nucleic  acid  the 
ribrose  is  either  burned  directly  or  else  converted  into  d-glucose.  Since 
the  formation  of  nucleic  acid  is  independent  of  any  pentose  of  the  diet, 


232  METABOLISM 

it  is  obvious  that  it  must  be  derived  from  d-glucose.  A  glance  at  the 
two  equations,  however,  does  not  indicate  how  this  is  attained. 

Pentose  is  rarely  found  in  the  urine,  supposedly  in  combination  with 
urea.  Pentosuria  is  usually  an  idiopathic  condition,  without  symptoms 
and  inclines  to  run  in  families.  Pentose  has,  however,  been  found  in 
the  urine  in  typical  diabetes,  side  by  side  with  d-glucose,  though  in 
much  smaller  amount.  The  variety  of  pentose  seen  in  idiopathic  pen- 
tosuria is  not  d-ribrose,  but  d-  and  1-arabinose  in  equal  amounts.  In 
one  case  1-arabinose  was  eliminated  alone. 

There  are  three  possible  explanations  of  pentosuria:  the  sugar 
might  be  of  alimentary,  of  glucolytic  or  of  nucleic  origin.  It  seems 
certain  that  the  pentose  is  not  derived  from  the  diet.  The  condition 
persists  despite  pentose-,  pentosan-,  or  carbohydrate-free  diet.  It  is 
not  exaggerated  by  the  administration  of  pentoses;  the  subjects  of 
this  curious  anomaly  burn  pentoses  in  a  normal  manner;  even  ingested, 
arabinose  is  burned  and  not  added  to  the  arabinose  of  the  urine.  As 
elsewhere  stated,  the  pentoses  of  the  diet  are  probably  converted  into 
d-glucose  in  the  intestinal  wall,  which  explains  this  finding.  It  is  clearly 
not  a  form  of  alimentary  melituria. 

If  the  pentosuria  were  of  nucleic  origin,  this  would  mean  that  some- 
where in  the  body  d-ribrose  is  converted  into  d-  and  1-arabinose,  instead 
of  being  burned  or  converted  into  d-glucose.  This,  of  course,  is  possible, 
as  we  know  experimentally  that  the  various  hexoses  are  convertible 
into  each  other,  and  sometimes  with  ease.  Nevertheless  the  stereo- 
isomeric  equations  for  these  pentoses  are  far  apart. 

If,  lastly,  the  pentoses  originate  in  d-glucose,  the  action  is  indeed 
an  abnormal  one.  The  occurrence  of  pentosuria  in  diabetes  (the  exact 
pentose  concerned  has  not  been  determined)  furnishes  us  with  an  illus- 
tration, however,  since  here  we  must  regard  the  pentose  as  derived 
from  d-glucose.  This  deflection  only  affords  another  illustration  of 
the  perversion  of  the  carbohydrate  metabolism  in  diabetes. 

Of  the  origin  of  the  pentose  in  the  body  as  utilized  in  the  synthesis 
of  nucleic  acid,  we  have  no  experimental  or  chemical  evidence.  It  is 
not  possible  to  believe  that  as  in  the  plant  it  can  be  built  up  from  formic 
acid.  It  is  difficult  to  believe  that  it  could  be  formed  from  glycerol. 
It  must  be  assumed  that  d-glucose  is  built  down  to  the  pentose.  Where 
and  how  this  is  accomplished  is  not  known.  Certain  bacteria  are  able 
to  form  1-xylose  from  d-glucuronic  acid. 


d-glucuronic  acid 

l-xylose 

COH 
HCOH 

COH 

HCOH 
HOCH 
HCOH 
CH2OH 

HOCH                    -► 
HCOH 
HCOH 
COOH 

C02 

COMBINED  SUGARS  OF  THE  TISSUES  233 

It  does  not  seem  possible  to  regard  this  conversion  as  illustrating  a 
type  of  reaction  to  which  we  could  appeal  in  explanation  of  the  forma- 
tion of  d-ribrose  from  d-glucose.  The  synthesis  of  nucleic  acid  is  in 
this,  as  in  the  derivation  of  purin  and  pyrimidin  from  protein,  a  most 
original  and  self-sufficient  process. 

Galactose. — Under  the  term  galactose  we  understand  d-galactose. 
Galactose  exists  to  a  limited  extent  in  plants,  in  the  forms  of  galacto- 
sids,  in  gums  of  a  starch-like  nature  termed  galactans  and  in  plant  amyl- 
oid. In  animals  galactose  exists  in  milk  sugar,  in  the  central  nervous 
system  and  in  the  peripheral  nerves,  in  true  mucins  (of  the  higher 
animals  as  well  as  in  such  mucins  as  the  covering  of  frog's  eggs)  and 
apparently  in  some  nuclei,  though  it  is  clear  that  galactose  plays  no 
such  role  in  the  nuclei  as  does  pentose.  It  is  not  present  in  the  blood 
or  circulating  fluids  or  in  the  urine.  When  galactose  is  injected  into 
the  circulation,  it  will  be  eliminated  only  in  part  in  the  urine,  if  at  all. 
From  this  it  is  apparent  that  the  body  can  burn  it  directly  or  convert 
it  into  d-glucose.  In  the  digestion  of  milk  sugar  or  of  the  galactose- 
yielding  carbohydrates  of  plants,  the  galactose  is  in  the  intestinal  wall 
(or  eventually  in  the  liver)  fully  converted  into  glucose.  And  so  far 
as  we  are  aware,  this  reaction  is  never  reversed  in  the  metabolism, 
though  it  is  reversed  in  special  tissues — in  the  mammae  and  in  the 
central  nervous  system.  Idiopathic  galactosuria  is  unknown;  alimentary 
galactosuria  has  been  reported  in  a  few  cases  of  hepatic  disease.  It 
is,  of  course,  possible  that  on  a  diet  of  milk,  the  intestinal  wall  might 
be  overflooded  with  galactose  and  some  pass  into  the  portal  circula- 
tion, later  to  pass  through  the  diseased  liver  into  the  general  circulation, 
carried  to  the  kidney  and  there  eliminated.  But  the  reported  cases  of 
galactosuria  should  be  viewed  with  suspicion,  because  of  the  methods 
of  analysis  used.  For  the  positive  separation  of  galactose  from  glucose 
and  its  identification,  several  methods  must  be  employed:  the  rota- 
tion of  the  plane  of  polarized  light,  the  refractive  index,  the  formation 
of  mucic  acid,  the  formation  of  galactose-a-methyl  phenylhydrazone, 
and  the  fermentation  test  with  a  culture  of  Saccharomyces  Ludwigii 
that  has  been  recently  tested  on  galactose  and  glucose. 

The  galactose  fraction  of  the  milk  sugar  of  the  lactating  animal  is 
formed  from  the  blood  glucose  in  the  cells  of  the  mammary  gland. 
It  is  the  reversal  of  the  reaction  whereby  in  digestion  milk  sugar  is 
split  into  glucose  and  galactose,  and  the  galactose  then  converted  into 
glucose.  The  cells  of  the  mammary  gland  convert  glucose  obtained 
from  the  blood  into  galactose,  and  then  combine  with  this  other  glucose 
from  the  blood  to  form  milk  sugar.  It  is  a  purely  localized  function; 
and  so  far  as  known,  galactose  never  escapes  into  the  circulation,  though 
as  will  be  soon  elucidated,  the  finished  milk  sugar  often  does.  Extirpa- 
tion of  the  mammae  of  an  actively  lactating  animal  is  followed  by  a 
transcent  hyperglucemia,  with  glucosuria;  glucose  alone  appears  in 
excess  in  the  blood  and  in  the  urine.  It  is  as  though  the  sugar-forming 
functions  of  the  body  had  established  a  certain  high  plane  of  produc- 


234  METABOLISM 

tion  of  glucose,  to  supply  the  usual  needs  of  fuel  and  the  extraordinary 
demands  of  the  breast  glands;  and  on  the  latter  being  suddenly  removed, 
the  overproduction  of  glucose  could  not  be  promptly  shut  down.  The 
formation  of  milk  sugar  is  independent  of  the  galactose  of  the  diet; 
nor  is  galactose  in  the  diet  utilized  directly  in  milk  formation.  In  other 
words,  so  far  as  the  sugar  is  concerned,  milk  is  no  better  a  food  for  the 
nursing  mother  than  any  food  that  contains  the  available  carbohydrates; 
in  whatever  state  ingested,  carbohydrate  must  be  converted  into  glucose 
and  the  galactose  formed  in  the  mammae  from  the  glucose. 

Galactose  exists  in  the  central  nervous  system  and  in  the  peripheral 
nerves  in  stable  combination  with  the  lipoids.  The  amounts  are  not 
striking,  but  the  combination  is  fundamentally  essential.  So  little  is 
known,  despite  extensive  and  intelligent  investigation  of  these  lipoids 
of  the  nervous  system,  that  we  are  not  in  a  position  to  indicate  with 
what  manner  of  combination  we  are  here  concerned.  An  illustration 
will  make  this  plain.  On  analysis  of  the  white  matter  of  the  brain, 
after  a  series  of  procedures  a  substance  is  obtained  that  is  termed 
cerebron.  On  hydrolysis  this  splits  into  a  substance  termed  cerebronic 
acid,  sphingosis  and  galactose.    Thus  supposedly : 

C48H93N09  +  H20  =  C22H50O3  +  Ci7H35N02  +  C6H1206 

Neither  the  constitution,  the  molecular  weight  nor  even  the  elementary 
analysis  of  the  cerebron,  cerebronic  acid  or  the  sphingosis  is  under- 
stood. Galactose  may  be  also  obtained  from  other  fractions  of  the 
material  than  the  cerebron.  But  aside  from  all  this,  which  must  be 
clarified  by  future  research,  it  is  certain  that  we  deal  here  with  a 
combination  of  fundamental  importance.  Galactose  exists  also  in  the 
nervous  cells.  In  the  catabolism  of  the  nervous  tissues  the  galactose 
must  be  set  free,  and  so  far  as  we  can  judge  is  not  eliminated  in  the 
urine  unchanged,  since  we  have  evidence  that  the  body  tissues  and 
fluids  can  burn  it  or  convert  it  into  glucose,  most  probably  the  latter. 

The  galactose  in  mucin  and  in  the  nuclei  is  in  stable  combination, 
the  mucin  being  one  of  the  most  typical  of  the  so-called  glycoproteids. 
The  amount  of  galactose  present  is,  however,  very  small. 

The  formation  of  galactose  from  glucose  for  the  purpose  of  combina- 
tion with  lipoids,  mucin  and  nuclei  constitutes  the  best-known  anabolic 
processes  of  the  sugar  metabolism.  It  will  be  later  pointed  out  that 
glycogen  seems  to  bear  analogous  relations  to  protein,  though  as  a 
whole,  it  is  to  be  viewed  as  a  storage  form  of  sugar.  But  in  the  case 
of  galactose,  we  deal  with  an  anabolism  that  has  no  relations  to  the 
combustions  of  the  body  but  is  concerned  solely  with  the  formation  of 
chemical  complexes  of  the  highest  cellular  importance.  The  mechanism 
of  the  transformation  of  glucose  into  galactose  is  not  known.  It  is 
easy  in  the  laboratory  to  form  glucose  from  galactose  and  possible  also 
to  form  galactose  from  glucose.  The  localization  of  the  formation 
of  glucose  from  galactose  in  the  intestinal  wall,  and  of  the  formation  of 


COMBINED  SUGARS  OF  THE  TISSUES  235 

galactose  from  glucose  in  the  central  nervous  system,  mammary  glands, 
mucin-forming  cells,  and  in  nuclei  indicates  that  special  conditions  are 
requisite. 

Fructose  (Levulose). — Although  fructose  is  not  an  anabolic  state 
of  glucose  it  may  be  appropriately  considered  here.  Under  the  term 
fructose  we  understand  d-fructose.  Fructose  is  present  in  nature  in 
the  form  of  cane  sugar,  and  in  all  fruits  and  in  complex  polysaccharids 
that  are  termed  fructans,  of  which  inulin  is  an  illustration.  In 
digestion,  the  fructose  derived  from  fruits  and  from  cane  sugar  is  con- 
verted into  glucose  in  the  intestinal  wall  and  in  the  liver.  When 
fructose  is  introduced  into  the  blood,  it  is  eliminated  in  part  only  by 
the  kidneys.  The  tissues  apparently  have  power  to  convert  fructose 
into  glucose.  There  is  evidence  that  the  body  does  not  burn  fructose 
directly,  but  only  after  conversion  into  glucose.  Unlike  galactose, 
fructose  has  no  metabolic  relations  and  is  not  to  be  found  in  the  tissues 
of  the  body  except  in  circulation. 

Fructose  sometimes  appears  in  the  urine.  Three  types  of  fructosuria 
are  to  be  distinguished.  Alimentary  fructosuria  is  seen  in  not  a  few 
cases  of  diabetes,  in  some  diseases  of  the  liver,  and  sometimes  unasso- 
ciated  with  any  disease.  It  may  occur  in  uncomplicated  pregnancy. 
It  is  due  simply  to  the  fact  that  following  the  ingestion  of  a  large  amount 
of  cane  sugar,  the  intestinal  wall  is  overwhelmed  and  the  liver  does 
not  complete  the  conversion  of  levulose  into  glucose.  It  can  be  pro- 
voked, experimentally,  by  ablation  of  the  larger  portion  of  the  liver; 
by  ligation  of  the  portal  vein;  is  noted  in  some  cases  of  Eck's  fistula; 
and  clinically  is  so  often  present  in  chronic  degenerative  diseases  of 
the  liver,  as  cirrhosis,  as  to  constitute  a  diagnostic  test.  It  is  not  seen 
in  the  acute  degenerative  diseases  of  the  liver,  such  as  acute  yellow 
atrophy  and  eclampsia.  Undoubtedly  most  of  the  instances  of  fructo- 
suria seen  in  diabetes  are  alimentary  fructosuria  associated  with  hepatic 
diseases.  Rarely,  however,  an  alimentary  fructosuria  is  seen  in  which 
there  are  no  indications  of  hepatic  disease. 

Mixed  melituria  is  common  in  pronounced  diabetes,  fructose  and 
glucose  being  eliminated  side  by  side,  the  former  always  in  the  lesser 
amounts.  The  effect  of  restriction  of  the  carbohydrate  input  is  more 
markedly  evinced  upon  the  fructosuria  than  upon  the  glucosuria. 
There  is  no  doubt  that  mixed  melituria  is  an  unfavorable  sign  in 
diabetes.  The  meaning  is  probably  defective  hepatic  function.  The 
usual  case  of  diabetes  converts  fructose  into  glucose  quite  as  in  the 
normal;  the  inability  to  do  so  constitutes  only  an  added  defect. 

Finally,  cases  of  supposedly  idiopathic  fructosuria  have  been  reported, 
in  which  the  condition  is  stated  to  have  persisted  in  the  absence  of 
fructose  from  the  diet.  These  cases  have  not  been  properly  studied. 
Not  only  is  it  necessary  to  exclude  all  fructose-carrying  foods,  it  is 
also  necessary  to  test  the  influence  of  different  sugars  with  a  carbo- 
hydrate-free diet.  There  is  one  further  explanation  that  has  been  over- 
looked.   The  fructans,  like  inulin,  are  supposed  to  be  resistant  to  the 


236  METABOLISM 

ferments  of  the  alimentary  tract,  though  easily  hydrolysed  by  bacteria. 
This  might  serve  as  the  source  of  the  fructose.  The  tests  commonly 
applied  for  the  identification  of  fructose  are  not  reliable.  The  color 
tests  and  the  reactions  with  the  different  salts  of  copper  are  not  reliable 
criteria.  One  must  determine  the  rotation  of  the  plane  of  polarized 
light,  ascertain  the  refractive  index,  demonstrate  the  presence  of  the 
keton  group,  form  the  characteristic  fructose-methyl-phenyl-hydrazone 
and  apply  the  fermentation  test  with  a  proved  .culture  of  Sacch.  mem- 
branefsecans.  If  a  fructosuria  were  determined  to  exist  under  controlled 
conditions  in  the  diet  (on  a  diet  of  glucose  and  casein  for  example), 
it  would  be  explicable  only  as  a  reversion  of  the  reaction  whereby 
normally  glucose  is  formed  from  fructose.  This  reversion  is  easily 
accomplished  in  the  laboratory.  But  so  long  as  we  possess  in  the  body 
no  demonstration  of  such  a  conversion  normally,  one  must  be  rigid 
in  the  application  of  the  analytical  criteria.  No  idiopathic  fructosuria 
has  thus  far  been  demonstrated  to  be  of  metabolic  origin.  Fructose 
has,  however,  been  isolated  from  the  blood  of  the  non-diabetic  subject. 

Chondroitin. — In  cartilage,  bone,  tendons,  connective  tissues  of  the 
type  of  fascia?,  reticulin,  hyalin  layer  of  bloodvessels  and  especially  in 
the  pathological  material  termed  amyloid  is  an  ethereal  sulphuric  acid 
termed  chondroitin-sulphuric  acid.  Traces  seem  to  occur  also  in  the 
urine.  When  this  conjugated  sulphuric  acid  is  split  by  heating,  an 
amino-polysaccharid  is  recovered  that  is  evidently  a  highly  complex 
anabolized  form  of  carbohydrate.  The  substance  is  so  different  from 
glycogen  that  it  is  better  to  regard  it  as  a  substance  anabolized  from 
glucose  than  as  a  modified  glycogen.  Of  its  internal  constitution 
nothing  is  known;  of  its  derivation  nothing  is  known. 

An  apparently  somewhat  similar  substance  has  been  obtained  from 
the  liver,  spleen,  kidneys,  pancreas,  and  mammary  glands,  termed 
glucothionic  acid.  It  is  also  an  ethereal  conjugation  of  a  carbohydrate 
with  sulphuric  acid.  In  the  case  of  glucothionic  acid,  the  carbohydrate 
does  not  seem  to  be  a  polysaccharid.  On  the  other  hand,  it  has  no 
relation  to  the  pentose  of  nuclein. 

The  last  of  the  anabolic  states  of  glucose  is  d-glucosamin.  This  is 
an  amino-sugar,  a  combination  of  an  amino-group  with  glucose. 

Glucose  Glucoaamin 

CHO  CHO 

HCOH  HCOH 

HOCH  HOCH 

HCOH  HCOH 


HC 


OH  HCNH2 

CH2OH  CH2OH 

It  exists  in  complex  combination  in  the  chitins  of  the  shells  of  many 
crustaceans  and  in  the  wings  of  insects.     Glucosamin  exists  in  most 


THE  DERIVATION  OF  THE  SUGAR  OF  THE  BLOOD         237 

proteins.  The  glucoproteins  contain  20  to  30  per  cent.,  ovalbumin 
10  per  cent.,  the  serum  albumin,  globulins,  and  myosins  contain  traces, 
while  casein  is  free  of  it,  as  is  codfish  flesh.  In  its  native  state  it 
exists  probably  as  a  polysaccharid.  Galactosamin  usually  coexists  with 
glucosamin  in  the  true  mucins.  It  is  also  to  be  obtained  in  the  hydro- 
lysis of  the  bodies  of  bacteria.  It  is  sometimes  found  in  the  contents 
of  cystic  tumors  of  the  broad  ligament  and  in  other  mucinaginous 
neoplasms.  Feeding  experiments  designed  to  produce  such  conditions 
have  not  been  successful.  It  seems  clear  that  the  amino-sugar  is  formed 
in  situ  in  the  tissues  where  it  occurs,  and  is  thus  a  typical  anabolic 
product  of  glucose. 

The  Catabolism  of  the  Special  Tissue  Sugars. — Pentose,  galactose, 
galactosamin,  and  glucosamin  we  have  named  as  the  anabolic  products 
of  glucose  that  exist  in  the  state  of  primary  sugars.  They  are  constit- 
uents of  tissues  and  cells.  What  becomes  of  them  when  the  cells  and 
tissues  of  which  they  are  a  part  undergo  catabolism?  We  do  not  know. 
They  might  be  converted  into  glucose  by  the  reversions  of  the  reactions 
through  which  they  were  formed ;  they  might  be  eliminated  unchanged 
as  end  products.  That  they  could  be  burned  directly  is  hardly  to  be 
regarded  as  probable.  The  amounts  involved  are  so  small  that  one 
could  not  hope  to  detect  them  in  the  urine.  The  products  of  catabolism 
are  so  rarely  utilized  in  the  organism  that  from  the  general  point  of 
view  one  would  be  inclined  to  the  opinion  that  these  sugars  (except 
the  glucosamin)  are  eliminated  unchanged. 


THE  DERIVATION  OF  THE  SUGAR  OF  THE  BLOOD 

Glucose  is  the  substrate  of  the  sugar  metabolism  of  the  body;  all 
the  carbohydrates  of  the  diet  are  converted  into  it,  and  from  it  all 
the  forms  of  carbohydrate  of  the  tissues  are  formed.  Is  the  carbo- 
hydrate of  the  diet  the  sole  source  from  which  the  glucose  of  the  blood 
is  derived?  This  is  a  fundamental  question,  and  one  that  for  years 
presented  seemingly  interminable  experimental  difficulties  to  the 
investigator.  We  are  now  on  clear  ground  in  part;  and  in  any  event 
the  facts  known  are  of  such  nature  as  to  enable  us  to  consider  in  a 
provisional  manner  the  entire  problem. 

Derivation  of  Sugar  from  Proteins. — Obviously,  there  are  two  further 
sources  for  the  derivation  of  glucose  than  the  carbohydrates  of  the  diet; 
the  proteins  and  the  fats.  When  we  recall  that  a  half  century  ago  it 
was  the  ruling  view  that  the  fattening  of  animals  was  accomplished 
through  the  protein  metabolism,  it  is  all  the  more  interesting  to  realize 
how  difficult  it  has  been  within  recent  years  to  prove  that  sugar  can 
be  formed  from  protein.  In  fact,  it  has  been  only  since  our  conception 
of  the  internal  constitution  of  the  molecule  of  protein  became  definable, 
that  it  has  been  possible  to  so  arrange  the  experiments  and  control 
the  variables  as  to  demonstrate  the  formation  of  sugar  from  protein. 


238  METABOLISM 

Proteins  are  composed  of  linkings  of  amino-acids.  And  it  is  from  the 
fatty  acids  of  these  amino-acids  that  glucose  is  formed.  When  a  protein 
is  broken  down  in  catabolism,  it  is  split  by  hydrolysis  into  the  component 
amino-acids.  From  this  point  on  there  are  two  chemical  possibilities: 
the  amino-acids  may  be  split  by  deaminization,  the  nitrogenous  fraction 
converted  into  urea  and  the  oxy-fatty  acids  burned  directly;  or  sugar 
may  be  formed  from  the  oxy-fatty  acids  or  from  the  amino-acids,  and 
this  sugar  then  burned.  The  body  can,  of  course,  burn  all  the  fatty 
acids  that  are  encountered  in  the  molecule  of  protein;  the  body  can 
burn  all  the  amino-acids  that  are  to  be  obtained  from  the  molecule  of 
protein.  Direct  experiments  also  prove  that  while  the  body  does  not 
form  sugar  from  the  simple  lower  fatty  acids,  it  does  form  sugar  from 
some  amino-acids  introduced  from  without.  From  the  standpoint 
of  energy,  there  is  no  gain  to  the  body  in  first  converting  the  amino- 
acids  into  sugar  and  burning  them  in  that  state;  but  it  is  a  question 
of  physiological  fact  and  not  of  teleology.  On  the  other  hand,  it  is 
clear  that  all  the  carbon  of  the  molecule  of  protein  is  not  converted 
into  sugar;  some  of  the  oxy-fatty  acids  are  burned  directly.  In  other 
words,  all  of  the  amino-acids  derived  in  the  hydrolysis  of  protein  are 
not  sugar  builders.  From  the  standpoint  of  general  theory,  it  would 
be  very  simple  if  it  could  be  assumed  that  all  the  carbon  of  the  mole- 
cule of  protein  (and  of  the  fats)  were  converted  into  sugar.  This  would 
make  sugar  the  sole  fuel  of  the  metabolism.  We  are  not,  however, 
warranted  in  assuming  this  position,  though  there  are  general  considera- 
tions and  qualitative  arguments  that  make  the  view  very  attractive. 

What  is  the  crucial  experiment  that  proves  that  sugar  is  formed 
from  protein?  A  dog  is  first  fasted  until  poor  in  glycogen.  It  is  then 
made  diabetic  by  ablation  or  destruction  of  the  pancreas.  If  now  the 
dog  be  maintained  upon  a  carbohydrate-free  diet,  containing  only 
protein  free  of  preformed  carbohydrate  (as  casein),  and  the  sugar  of 
the  urine  estimated  day  after  day,  in  favorable  cases  where  it  is  possible 
to  keep  the  animal  alive  for  a  long  time,  it  will  be  found  that  the  amount 
of  sugar  eliminated  in  the  urine  exceeds  greatly  the  sugar  that  could 
have  been  derived  from  all  forms  of  storage  of  carbohydrate  in  the 
body  of  the  dog.  The  sugar  eliminated  in  the  urine  of  such  a  dog  must 
have  come  from  protein  or  from  fat.  By  direct  experiment,  it  is  possible 
to  follow  the  formation  of  sugar  from  certain  amino-acids.  And  in 
the  dog  with  phloridzin  intoxication,  it  is  also  possible  to  show  in  toto 
the  formation  of  sugar  from  protein  and  directly  also  the  conversion  of 
certain  amino-acids  into  glucose.  The  question  that  concerns  us  here 
relates  to  the  extent  that  this  occurs  in  normal  metabolism.  Do  the 
experimental  facts  hold  for  the  normal,  or  do  they  merely  illustrate 
adaptations  to  extraordinary  conditions?  If  they  are  phenomena  of  the 
normal  metabolism,  what  are  the  quantitative  relations,  what  amounts 
of  sugar  may  be  normally  derived  from  the  protein  metabolism? 

Today  it  must  be  regarded  as  certain  that  the  formation  of  sugar 
from  amino-acids  is  a  fact  of  normal  metabolism,  and  not  an  adapta- 


THE  DERIVATION  OF  THE  SUGAR  OF  THE  BLOOD         239 

tion  to  meet  an  experimental  or  pathological  condition.  The  ultimate 
cause  of  glucosuria  in  the  diabetic  is  the  inability  to  burn  sugar.  The 
cause  of  glucosuria  in  phloridzin  intoxication  is  abolition  of  renal 
retention  of  the  glucose  in  the  blood.  The  conversion  of  certain  amino- 
acids  into  sugar  holds  for  the  postmortem  experiment  of  perfusion 
through  the  liver  as  well  as  for  the  two  conditions  of  diabetes  and 
phloridzin  intoxication.  Since  it  is  inconceivable  that  the  formation 
of  sugar  from  amino-acid  should  be  an  adaptation  in  three  such  different 
conditions  of  metabolism  and  experimentation,  we  are  forced  to  regard 
it  in  all  three  as  a  physiological  procedure,  and  to  assume  that  under 
all  known  conditions,  physiological  and  pathological,  sugar  is  formed 
from  the  amino-acids  derived  from  the  catabolism  of  protein. 

What  amounts  of  sugar  are  thus  derived?  Is  the  total  carbon  of  the 
protein  molecule  converted  into  the  state  of  sugar?  No  positive  answer 
can  be  given;  to  date,  however,  it  seems  most  probable  that  only  a 
fraction  of  the  amino-acids  is  converted  into  sugar.  A  fraction  is 
burned  directly.  Whether  this  means  that  certain  amino-acids  are 
not  sugar  builders;  or  whether  it  means  that  some  condition  limits  the 
conversion  of  these  amino-acids  into  sugar,  is  not  known.  The  experi- 
mental solution  of  the  question  has  been  approached  in  two  ways:  one 
by  the  determination  of  the  quantity  of  sugar  that  can  be  gotten  out 
of  a  unit  of  protein,  under  constant  conditions  of  experimentation; 
and  the  other  by  testing  the  individual  amino-acids  for  their  chemical 
qualifications  as  sugar  builders.  The  molecule  of  common  protein 
contains  about  50  per  cent,  of  carbon.  If  this  were  all  converted  into 
sugar,  that  would  equal  the  formation  of  1.25  grams  of  sugar  from 
1  gram  of  protein.  Or  stated  in  the  form  of  the  nitrogen:  glucose 
ratio,  it  would  mean  that  1  gram  of  nitrogen  in  protein  would  corre- 
spond to  8  grams  of  sugar.  Now  this  is  far  more  than  is  ever  seen  in 
experiment  (though  it  has  been  reported  in  human  diabetes),  in  which 
the  formation  of  four  parts  of  glucose  to  one  part  of  nitrogen  in  the 
protein  (nitrogen:  glucose  ratio  1  :  4)  seems  to  be  the  limit.  It  is, 
however,  unfair  to  assume  that  all  the  protein,  under  the  conditions 
of  the  experiment,  underwent  catabolism;  how  much  may  have  been 
retained  in  the  body  for  purposes  of  the  protein  metabolism  cannot 
be  accurately  determined.  The  quantitative  experiment,  therefore, 
indicates  that  at  least  half  of  the  carbon  of  the  protein  molecule  may 
be  converted  into  sugar;  it  does  not  inform  us  whether  more,  or  how 
much  more,  might  be  converted. 

The  qualitative  method  of  experimentation  (to  be  later  discussed  in 
detail)  consists  in  testing  the  several  amino-acids  for  their  converti- 
bility into  glucose.  There  are  in  the  protein  molecule  nearly  twenty 
different  amino-acids.  Many  of  these  have  not  been  tested.  Some  of 
the  most  prominent  have  been  tested  with  positive  results.  Others 
are  known  not  to  yield  sugar.  From  these  results  it  is  clear,  for  the 
present  at  least,  that  no  decision  may  be  reached  as  to  the  amount  of 
sugar  that  is  actually  derived  from  the  protein  of  the  daily  metabolism. 


240  METABOLISM 

If  the  total  carbon  of  the  protein  were  converted  into  sugar,  a  man 
of  70  kilos  weight  on  a  daily  ration  of  70  grams  of  protein,  would  derive 
from  this  source  about  100  grams  of  sugar  daily.  If  the  amount  of 
sugar  were  calculated  according  to  the  highest  nitrogen-glucose  ratio 
that  is  to  be  observed  in  experimental  diabetes,  about  50  grams  would 
be  daily  so  derived.  These  amounts  of  sugar  would  yield  corre- 
spondingly 400  and  200  Calories  of  heat — but  a  small  fraction  of  the 
total  heat  requirements  of  the  body.  The  average  diet  of  a  man  of 
70  kilos,  on  a  ration  of  70  grams  of  protein,  will  contain  400  to  500 
grams  of  carbohydrate. 

As  will  be  pointed  out  in  the  discussion  of  diabetes,  the  quantitative 
relations  are  there  different  and  of  vastly  greater  importance.  Since 
the  diabetic  is  thrown  upon  the  combustion  of  protein  to  a  much  greater 
extent  than  is  the  normal  body,  the  amount  of  sugar  derived  there- 
from may  be  two  or  three  times  the  amount  thus  derived  in  the  normal 
body.  It  is  this  sugar,  which  the  diabetic  body  cannot  burn,  that 
accounts  for  the  persistence  of  glucosuria  on  a  carbohydrate-free  diet; 
and  it  is  the  loss  of  this  sugar  that  reduces  so  greatly  the  efficiency  of 
the  combustion  of  protein  in  the  diabetic  organism. 

Derivation  of  Sugar  from  Fats. — Is  sugar  derived  from  fat  in  the 
animal  body?  This  is  a  fundamental  question,  but  one  for  the  future. 
That  fat  is  formed  from  sugar  both  in  plants  and  animals  is  not  to  be 
questioned.  That  in  plants  the  reversion  of  this  reaction,  the  forma- 
tion of  sugar  from  fat,  occurs,  is  also  not  to  be  questioned.  This  process 
is  easily  to  be  observed  in  the  germination  of  seeds  of  all  kinds.  Starch 
is  in  seeds  the  proximate  form  of  storage;  fat  is  the  ultimate  form  of 
storage,  in  some  seeds  more  than  in  others.  When  the  seed  under- 
goes germination,  the  starch  is  first  converted  into  sugar;  thereafter 
the  fat  is  converted  into  sugar,  attended  with  the  evolution  of  carbon 
dioxid.  The  carbon  which  the  growing  plant  obtains  from  the  carbon 
dioxid  of  the  air,  the  germinating  seed  obtains  in  part  from  its  fat. 
The  entire  process,  the  reactions  in  each  direction,  can  be  well  observed 
in  the  ripening  and  germination  of  the  nuts. 

Does  such  a  reaction  occur  in  the  animal  body?  We  do  not  know. 
As  will  be  pointed  out  in  the  discussion  of  the  fat  metabolism,  we  do 
not  know  positively  the  reactions  through  which  fat  is  burned  in  the 
body.  Obviously,  it  might  be  burned  directly  as  commonly  believed; 
or  it  might  be  first  converted  into  sugar.  Could  this  last  eventuality 
be  demonstrated,  it  would  simplify  enormously  our  conception  of  the 
fuel  combustion  of  the  body.  Up  to  the  present,  there  is  no  way  of 
showing  that  sugar  is  formed  in  the  body  from  fat.  There  is  confessedly 
also  no  way  of  proving  that  it  is  not  so  formed.  When  the  diabetic 
dog  eliminates  more  sugar  than  can  be  accounted  for  by  the  stored 
carbohydrates  in  the  body,  the  assumption  that  this  sugar  is  all  formed 
from  protein  and  none  from  fat  is  simply  an  inference  along  the  line 
of  least  resistance.  There  is  no  possibility  for  the  conversion  of  fat 
into  sugar  in  the  processes  of  digestion;  the  fat  is  resorbed  as  such. 


THE  DERIVATION  OF  THE  SUGAR  OF  THE  BLOOD  241 

There  is  also  no  likelihood  of  the  formation  of  sugar  from  protein  in 
the  processes  of  digestion.  It  is  in  both  instances  a  derivation  in  metab- 
olism only.  If  sugar  were  formed  from  fat,  in  a  relation  of  simple 
reversion  of  the  reaction  whereby  fat  is  formed  from  sugar,  1  gram 
of  fat  would  yield  nearly  2  grams  of  sugar. 

In  a  body  whose  metabolic  processes  are  being  normally  maintained 
by  the  foodstuffs,  the  sugar  of  the  blood  is  derived  in  large  part  from 
the  carbohydrates  of  the  diet,  not  over  50  or  at  the  most  100  grams 
being  derivable  from  the  protein  that  is  daily  undergoing  catabolism. 
When  for  any  reason  the  metabolism  of  the  body  is  not  being  fully 
supported  by  the  foodstuffs,  we  are  justified  in  the  inference  that  more 
sugar  is  derived  from  protein  in  proportion  to  the  greater  catabolism  of 
tissue  protein;  whether  when  the  fats  of  the  body  are  burned  sugar  is 
formed,  can  be  neither  affirmed  nor  denied. 

The  Disaccharids  in  Metabolism. — Cane  Sugar  or  Saccharose. — Specu- 
lation has  long  been  rife  concerning  the  possibility  of  the  entrance  of 
unchanged  foodstuffs  into  the  circulation  through  breaks  in  the  surface 
of  continuity  of  the  mucosa  of  the  alimentary  tract,  as  in  the  case  of 
ulcerations.  For  the  proteins,  the  matter  may  have  an  important 
bearing,  as  will  be  elsewhere  elucidated,  since  the  entrance  of  native 
foreign  protein  might  lead  to  the  establishment  of  anaphylaxis.  So 
far  as  known,  starch  under  no  circumstances  enters  the  circulation. 
There  is  likewise  no  evidence  that  the  disaccharids  ever  enter  the 
circulation  through  ulcerations.  They  do,  however,  enter  the  circula- 
tion when  an  excessive  overload  is  placed  upon  the  resorption  membrane. 
It  is  possible  by  the  ingestion  of  large  amounts  of  disaccharids,  to 
intensify  the  concentration  of  the  sugars  in  the  contents  of  the  intestine, 
leading  to  such  high  velocity  in  resorption  as  to  outrun,  so  to  speak, 
the  cleavage  reactions  that  normally  occur  within  the  intestinal  wall. 
In  a  word,  it  is  possible  to  absorb  a  disaccharid  more  rapidly  than  it 
can  be  split  into  its  component  primary  sugars.  This  does  not  seem 
true  of  all  individuals,  but  it  is  certainly  true  of  many  normal  subjects. 
Such  a  thing  never  occurs  in  connection  with  the  digestion  of  starch. 
No  matter  how  massive  the  meal  of  starch,  the  rate  of  conversion  into 
maltose  is  so  slow  that  the  maltose  in  resorption  is  always  converted 
into  glucose. 

Cane  sugar  or  saccharose  is  normally  not  a  constituent  of  metab- 
olism. By  this  we  understand  that  when  ingested  as  such,  in  the 
form  of  the  sugar  of  the  table  or  in  the  fruits  in  which  it  is  contained, 
it  is  always  completely  split  in  the  processes  of  digestion,  the  fructose 
fraction  is  converted  into  glucose,  and  thus  the  entire  product  in  the 
circulation  is  glucose.  When  cane  sugar  is  introduced  into  the  circula- 
tion, even  in  small  amounts,  it  is  quantitatively  eliminated  by  the 
kidneys.  In  other  words,  the  body  cannot  hydrolyze  it  and  cannot 
burn  it  directly;  it  is,  therefore,  eliminated  like  a  foreign  body.  Under 
abnormal  conditions  of  diet,  and  possibly  in  abnormal  conditions  of 
the  alimentary  tract,  the  ingestion  of  large  or  even  moderate  amounts 
16 


242  METABOLISM 

of  saccharose  will  be  followed  by  melituria.  There  is  probably  a  point 
with  every  healthy  body  beyond  which  the  ingestion  of  cane  sugar  on 
the  empty  stomach  will  be  followed  by  melituria.  Sometimes  this 
limit  of  assimilation  may  be  as  low  as  100  grams;  usually  200  or  300 
grams  can  be  ingested  without  more  than  a  transient  trace  of  meli- 
turia. The  sugar  that  appears  in  the  urine  may  be  glucose,  fructose,  or 
cane  sugar  itself,  or  these  may  be  combined.  The  more  normal  type, 
if  such  an  expression  may  be  used,  would  be  saccharosuria,  though 
combined  melituria  is  seen  in  entirely  healthy  persons.  The  presence 
of  cane  sugar  in  the  urine  is  easily  established,  especially  if  it  be  there 
alone,  as  the  special  yeasts  will  not  ferment  it.  If  glucose  or  fructose 
be  present  also,  the  polariscope  will  give  definite  information.  The 
rotation  of  the  plane  of  polarized  light  should  be  noted  in  direction 
and  degree,  and  the  urine  then  acidulated  with  hydrochloric  acid  to 
about  tenth  normal  strength  and  boiled  under  a  reflux  condensor  for 
a  half  hour,  following  which  the  rotation  is  again  observed  after  the 
exclusion  of  birotation  by  the  addition  of  a  little  alkali.  A  shifting  of 
the  rotation  to  the  left  will  indicate  the  presence  of  saccharose.  Fehling's 
solution  is  also  reduced  by  the  inverted  sugar. 

The  commonly  accepted  explanation  of  alimentary  saccharosuria 
is  that  when  ingested  in  large  amount,  the  velocity  of  absorption 
exceeds  the  velocity  of  cleavage,  and  some  unsplit  sugar  reaches  the 
portal  circulation;  and  as  the  liver  is  not  believed  to  have  the  power 
of  splitting  cane  sugar,  saccharosuria  results.  It  has,  however,  been 
shown  by  experiment  that  if  the  thoracic  duct  be  ligated  in  a  dog,  it 
is  very  difficult  to  produce  alimentary  melituria.  From  this  experi- 
ment one  might  infer  that  under  the  conditions  of  excessive  ingestion 
of  sugar,  a  portion  is  resorbed  through  the  lacteal  system,  instead  of 
through  the  portal  system  as  normally.  When  one  considers  the 
minimal  amounts  of  cane  sugar  that  are  to  be  recovered  in  the  urine 
after  the  ingestion  of  half  a  pound,  this  explanation  does  not  appear 
improbable.  We  know,  however,  that  cane  sugar  injected  into  the 
portal  vein  is  not  hydrolyzed  in  the  liver,  but  is  eliminated  by  the 
urine. 

Maltose. — Maltose  does  not  exist  in  plants  except  in  traces.  Its 
occurrence  in  the  diet  is  referable  to  the  maltose  of  the  factory,  this 
sugar  being  largely  used  in  confections.  Although  it  is  a  stage  in  the 
conversion  of  starch  into  sugar,  this  stage  is  transient;  and  so  far  as 
known,  such  a  thing  as  the  accumulation  of  maltose  in  the  act  of  diges- 
tion or  in  metabolism  does  not  occur.  Normally  tissues  contain  traces 
of  maltose,  most  easily  demonstrated  in  the  muscles.  Injected  into  the 
circulation,  it  is  split  into  glucose,  and  the  procedure  is  tantamount  to 
the  injection  of  so  much  glucose.  Apparently  all  the  glands  of  the 
body,  as  well  as  the  muscles,  are  able  to  effect  this  hydrolysis  of  maltose 
to  glucose.  An  alimentary  maltosuria  occurs  under  the  conditions 
of  excessive  ingestion  described  for  cane  sugar,  and  in  about  the  same 
quantitative  relations.    The  sugar  eliminated  is  always  both  maltose 


THE  DERIVATION  OF  THE  SUGAR  OF  THE  BLOOD         243 

and  glucose  if  the  ingestion  be  excessive;  maltose  may  appear  alone 
if  the  ingestion  be  smaller. 

There  is  a  rare  form  of  maltosuria  that  is  not  alimentary.  In  a  few 
cases  of  diabetes  maltose  has  been  found  in  the  urine.  It  has  been 
also  noted  in  the  urine  following  ablation  of  the  pancreas  in  the  dog, 
and  has  been  reported  in  acute  pancreatic  disease  in  man.  Its  presence 
in  diabetes  might  be  simply  explained  as  the  result  of  the  law  of  mass 
action.  The  failure  to  remove  glucose  from  the  system,  in  a  chemical 
hydrolysis  of  maltose,  will  result  in  the  cessation  of  the  reaction  before 
all  the  maltose  is  split;  and  thus  in  the  hyperglucemia  of  diabetes,  we 
might  expect  maltose  to  be  present  in  more  than  the  normal  traces, 
and  to  be  eliminated  in  the  urine. 

Lactose. — The  relations  of  the  metabolism  to  lactose  are  quite  identical 
with  those  of  cane  sugar.  When  injected  into  the  circulation  it  is 
quantitatively  eliminated  in  the  urine.  When  injected  into  the  portal 
vein,  the  same  result  is  attained.  In  other  words,  the  tissues  cannot 
burn  it  and  cannot  hydrolyze  it.  It  is  frequently  present  in  the  urine; 
and  this  lactosuria  is  of  two  types — alimentary  and  lactational. 

Alimentary  lactosuria,  following  the  ingestion  of  even  excessive 
amounts  of  milk,  may  be  said  to  occur  rarely  in  the  normal  individual. 
In  invalids  with  reduced  powers  of  digestion,  in  whom  forced  feeding 
with  milk  is  attempted,  traces  of  lactose  may  appear  in  the  urine.  It 
is  common,  however,  in  different  forms  of  gastro-enteritis  in  children. 
While  it  does  not  occur  easily  in  the  normal  adult  on  ingestion  of  milk, 
it  is  easily  provoked  by  the  administration  of  milk  sugar  in  concentrated 
solution  on  the  empty  stomach;  as  a  matter  of  fact  lactosuria  is  more 
easily  provoked  than  is  saccharosuria.  In  this  case  the  sugar  in  the 
urine  is  nearly  always  lactose  alone;  galactose  does  not  occur,  and 
glucose  is  rare.  The  condition  is  due  to  the  velocity  of  resorption  being 
greater  than  the  velocity  of  cleavage,  or  to  the  fact  that  a  fraction  that 
had  escaped  cleavage  escapes  the  liver  also  by  being  absorbed  into  the 
lacteal  system.  As  stated,  however,  in  direct  experiment,  the  liver  is 
not  found  capable  of  splitting  milk  sugar. 

Lactational  lactosuria  is  very  common.  It  may  appear  during  the 
last  days  of  gestation  or  during  the  early  days  of  the  puerperium. 
It  is  made  more  prominent  by  anything  that  hinders  the  normal  forma- 
tion and  discharge  of  the  milk,  and  usually  disappears  when  lactation 
is  fully  established.  It  may  reappear,  or  appear,  when  the  child  is 
weaned,  or  if  for  any  reason  lactation  be  suddenly  suspended.  It  may 
be  provoked  sometimes  in  the  pregnant  woman  by  the  ingestion  of  a 
large  amount  of  glucose  or  cane  sugar,  which  serves  to  act  as  a  stimu- 
lant to  the  function  of  the  mammary  gland.  If  the  mammary  glands 
of  an  animal  be  removed,  lactosuria  cannot  occur. 

The  sugar  is  usually  not  present  in  large  amounts,  but  this  state- 
ment has  many  exceptions.  The  explanation  of  its  occurrence  is  very 
simple  and  obvious.  The  intra-acinal  pressure  becomes  excessive, 
and  the  milk  sugar  transudes  into  the  paraductal  spaces,  to  be  taken 


244  METABOLISM 

up  by  the  circulation  and  eliminated  because  the  body  cannot  utilize 
the  sugar.  The  occurrence  of  lactosuria  in  the  pregnant  or  nursing 
woman  is  made  quite  certain  if  the  urine  reduces  Fehling's  solution  but 
will  not  ferment  with  Saccharomyces  cerevisise. 


THE    STATE    OF    GLUCOSE   IN    THE    CIRCULATING    FLUIDS    AND 
TISSUES    OF    THE   BODY 

The  glucose  content  of  the  body  is  largely  in  the  circulating  fluids, 
en  route  to  the  organs  of  combustion.  According  to  our  best  informa- 
tion, this  glucose  is  in  the  free  chemical  state,  uncombined  with  any 
other  substance.  It  is  true  that  combinations  of  glucose  have  been 
described;  it  cannot  be  denied  that  such  exist  and  they  may  have  a 
great  importance.  These  descriptions  refer  to  glucose-protein  and 
glucose-lipoid  complexes.  Upon  the  basis  of  this,  it  has  been  further 
assumed  that  the  sugar  in  colloidal  state  was  not  subject  to  combustion, 
which  involved  only  the  free  sugar.  The  limit  of  colloidal  sugar,  accord- 
ing to  this  view,  would  be  the  limit  of  the  colloids  with  which  it  is 
combined;  and  for  diabetes  in  which  a  hyperglucemia  with  glucosuria 
exists,  it  has  been  assumed  that  the  amount  of  sugar  present  exceeds 
the  colloids,  or  at  least  the  combining  power  of  the  blood.  Continuing, 
the  further  assumption  was  made  that  the  kidney  retains  the  colloidal 
sugar,  and  permits  the  free  sugar  to  diffuse  into  the  urine.  For  the 
glucose-protein  complex,  the  data  are  meagre  in  amount  and  of  very 
doubtful  quality.  For  the  two  lipoid  combinations,  the  so  called 
jecorin  and  glucose  phosphatid,  something  more  can  be  said,  though 
even  here  from  the  purely  chemical  point  of  view  the  methods  have 
been  untrustworthy.  Lipoids  are  very  prone  to  carry  into  an  ethereal 
extract  small  amounts  of  crystalloids  in  the  watery  media  from  which 
they  are  isolated.  These  adsorption  inclusions  are  often  very  tenacious, 
and  simulate  chemical  combinations  to  a  surprising  degree.  For  the 
jecorin  and  glucose  phosphatid  we  have  no  such  data  on  the  chemical 
state  of  composition  that  we  possess,  for  example,  for  the  galactose 
lipoid  or  for  the  pentose  combination  in  nuclein.  While  granting  the 
probable  occurrence  of  such  combinations  and  without  restricting  in 
any  way  the  scope  of  their  possible  importance,  it  is  necessary  to  leave 
the  question  in  this  unsettled  state.  The  amounts  of  glucose  involved 
are  in  any  event  small,  a  mere  fraction  of  the  total  glucose  of  the  blood. 

The  glucose  in  the  cells  is  in  all  probability  also  largely  in  the  free 
chemical  state.  Since  all  cells  contain  glycogen,  and  since  the  methods 
for  the  demonstration  of  glucose  in  tissues  are  very  likely  to  convert 
glycogen  into  sugar,  the  data  bearing  on  the  amounts  of  glucose 
contained  within  cells  are  very  untrustworthy.  Certainly,  fixed  cells 
and  the  blood  cells  contain  far  more  glycogen  than  glucose.  There  is 
no  evidence  that  all  the  cells  that  contain  glycogen  utilize  it;  it  would 
be  there  as  the  result  of  mere  diffusion  of  sugar  from  the  circulation 


GLUCOSE   IN   CIRCULATION  FLUIDS  AND  TISSUES  OF  BODY     245 

fluids.  The  anabolic  process  whereby  glucose  is  converted  into  pentose 
in  the  regeneration  and  multiplication  of  the  nuclei,  is  quite  certainly 
accomplished  in  situ  within  the  cells;  the  amount  involved  is,  however, 
extremely  minute. 


THE  QUANTITY  OF  GLUCOSE  IN  THE  CIRCULATION  FLUIDS  AND 
TISSUES    OF   THE   BODY 

Accurate  quantitative  analyses  of  glucose  in  a  fluid  like  the  blood 
are  not  easy  or  especially  accurate.  The  glucose  content  of  the  blood 
of  different  animals  runs  from  0.05  to  0.1  per  cent.  In  man  the  content 
seems  to  lie  close  to  0.08  per  cent.  The  figure  is  apparently  quite  con- 
stant for  each  species.  To  what  fluctuations  it  may  be  subject  under 
different  conditions  of  nutrition,  diet,  metabolism,  climate,  and  in 
different  diseases  has  not  been  properly  studied.  The  blood  contains 
more  sugar  during  infancy  than  during  adult  life.  The  glucose  content 
of  cells  is  unquestionably  much  lower  than  that  of  the  blood  plasma. 

When  one  contemplates  the  fluctuations  in  the  combustion  of  sugar 
under  the  different  conditions  of  adaptation  in  the  heat  metabolism 
and  under  varying  stresses  of  work,  the  constancy  of  the  sugar  concen- 
tration of  the  blood  is  all  the  more  striking.  It  is  regulated  by  the 
coadaptation  of  three  factors:  combustion,  formation  from  glycogen, 
and  elimination  by  the  kidneys.  The  last-named  variable  is  seldom 
in  operation  under  ordinary  conditions.  The  relations  of  the  kidneys 
to  the  glucose  concentration  of  the  blood  may  be  compared  to  the 
relation  of  a  dam  to  the  waters  of  a  mill  pond.  When  the  level  of  the 
impounded  water  is  below  the  top  of  the  dam,  none  overflows;  when 
the  water  rises  above  that  level,  overflow  occurs  until  the  level  is 
reduced  to  that  of  the  dam.  In  the  kidney,  so  long  as  the  glucose 
concentration  does  not,  in  man,  exceed  about  0.1  of  1  per  cent.,  the 
kidney  is  impermeable  to  it.  But  when  the  glucose  concentration  rises 
above  this  level,  sugar  is  eliminated  by  the  kidney  until  the  content 
in  the  blood  is  lowered  to  the  normal  figure.  For  this  extremely  inter- 
esting mechanism  we  have  as  yet  no  explanation  in  the  theory  of  secre- 
tion. How  a  fixed  level  exists  in  the  kidney,  and  to  what  reductions 
it  may  be  subject,  is  not  well  known.  For  one  substance  in  particular, 
phloridzin,  it  is  established  that  it  causes  glucosuria  by  lowering  the 
level  of  retention;  or  in  the  case  of  profound  intoxication,  by  the  com- 
plete opening  of  the  floodgates,  so  that  practically  all  the  sugar  of  the 
blood  is  eliminated,  the  renal  power  of  retention  of  glucose  being 
apparently  lost.  This  matter  will  be  discussed  in  detail  later.  Wrhether 
in  any  of  the  incidental,  so-called  non-diabetic  forms  of  glucosuria, 
that  will  be  later  described,  a  similar  mechanism  is  operative;  or  whether 
all  of  these  naturally  occurring  forms  of  glucosuria  are,  like  the  diabetic 
glucosuria,  due  to  hyperglucemia,  is  not  known.  This  is  a  point  that 
from  the  standpoint  of  theory,  as  well  as  for  practical  reasons,  is  worthy 


246  METABOLISM 

of  investigation.     In  phosphorus  poisoning  the  sugar  content  of  the 
blood  sinks  to  almost  nothing,  due  to  the  abolition  of  glycolysis. 

The  comprehension  of  the  constant  concentration  of  glucose  in  the 
blood,  below  the  level  of  renal  elimination,  is  made  clear  in  outline, 
if  not  in  detail,  by  terming  it  an  equilibrium  in  a  reaction  system. 
The  combustion  of  sugar  is  of  two  types,  that  may  be  termed  induced 
and  forced.  Under  induced  combustion  we  understand  the  combustion 
in  the  resting  state,  the  basal  production  of  heat  required  to  maintain 
the  body  temperature  under  the  existing  conditions  of  heat  radiation 
and  dissipation.  By  forced  combustion  we  understand  the  production 
of  heat  in  excess  of  this,  due  to  voluntary  muscular  exertion;  and 
followed,  of  course,  since  the  body  temperature  remain  normal,  by  an 
adaptation  for  proportionately  increased  heat  radiation  and  dissipa- 
tion. Whether  the  combustion  be  induced  or  forced  in  type,  the  seat 
of  the  combustion  is  certainly  in  large  part  in  the  muscular  system. 
The  concentration  of  glucose  in  the  blood  is-  maintained  by  the  con- 
version of  glycogen  into  sugar.  When  the  momentary  rate  of  combus- 
tion is  increased,  proportionately  more  glycogen  is  converted  into  sugar 
and  the  concentration  thus  maintained;  when  the  rate  of  combustion 
is  reduced,  less  glycogen  is  converted  into  sugar  and  hyperglucemia 
thus  avoided.  Just  as  in  a  chemical  system  operating  under  the  law 
of  mass  action,  we  can  accelerate  the  velocity  of  the  reaction  from 
substrate  to  product  by  the  removal  of  the  product;  so  when  the 
product  sugar  is  removed  by  combustion,  we  observe  the  conversion 
of  glycogen  to  sugar  accelerated.  If  the  products  are  not  removed,  or 
in  the  case  of  the  glucose  not  used  and  accumulate,  then  the  reaction 
of  substrate  to  product  becomes  retarded.  The  actual  point  of  equi- 
librium, in  a  system  in  catalytic  reaction,  depends  upon  the  relations 
of  substrate  concentration,  product  concentration,  and  ferment  con- 
centration. In  other  words,  the  velocity  of  formation  of  glycogen  into 
sugar  in  the  cells  is  a  function  of  the  amount  of  glycogen  (which  in  the 
reaction  sense  may  be  termed  constant),  of  the  ferment  concentration 
(which  in  the  normal  case  is  also  probably  constant),  and  of  the  con- 
centration of  glucose  within  the  cells.  Now  the  concentration  of 
glucose  within  the  cell  will  depend  upon  the  concentration  of  glucose 
in  the  circulation  fluids.  And  if  the  sugar  there  is  rapidly  removed 
by  combustion,  then  the  diffusion  of  glucose  from  the  cell  into  the 
circulation  will  be  rapid,  and  the  consequent  lowering  of  the  glucose 
concentration  within  the  cell  would  lead  to  acceleration  of  the  reaction 
of  conversion  of  glycogen  into  glucose.  One  additional  factor  in  further 
increasing  the  reaction  would  lie  in  an  increase  in  the  glycolytic  fer- 
ment in  the  cells  in  which  the  conversion  of  glycogen  into  sugar  occurs. 
From  the  standpoint  of  the  theory  of  the  law  of  mass  action  applied 
to  the  catalytically  accelerated  reaction,  the  constant  concentration 
of  glucose  in  the  circulating  fluids  of  the  body  presents  no  difficulties. 
That  the  process  has  not  been  experimentally  reproduced,  is  a  question 
of  chemical  and  experimental  difficulties.     The  quantitative  relations 


FORMATION  OF  GLYCOGEN  IN  CARBOHYDRATE  METABOLISM   247 

of  the  conversion  of  glycogen  to  sugar  are  easily  stated.  A  body  of 
150  pounds,  on  a  fixed  protein  ration  of  1  gram  of  protein  per  kilo,  and 
being  supported  by  the  combustion  of  sugar  alone  and  not  of  fat,  would 
burn  in  the  course  of  a  day  of  leisurely  activity  some  500  grams  of 
sugar.  This  corresponds  to  the  burning  of  about  6  milligrams  per 
second.  While  the  molecular  weight  of  glycogen  is  not  known,  analytical 
results  indicate  that  about  9  parts  of  glycogen  will  yield  10  parts  of 
sugar.  While  on  the  one  hand,  it  is  clear  that  the  formation  of  6  milli- 
grams of  sugar  from  glycogen  per  second  in  a  reaction  system  as  large 
as  the  human  body  is  chemically  a  trifling  accomplishment,  it  is  equally 
clear  that  the  maintenance  of  the  station  of  equilibrium  is  an  opera- 
tion of  great  delicacy  and  striking  mutability.  In  the  opinion  of  the 
writer,  the  retention  of  glucose  in  the  plasma  of  the  blood  by  the  kidneys 
is  an  expression  of  semipermeability  resting  upon  a  physico-chemical 
basis,  and  is  not  due  to  an  assumed  colloidal  combination  of  glucose. 
The  idea  that  diffusible  sugar  would  pass  through  the  kidney  and  only 
colloidally  combined  sugar  could  be  retained  is  too  obvious,  and  in 
addition  is  devoid  of  a  proper  foundation.  As  stated,  it  is  quite  certain 
that  the  larger  fraction  of  glucose  in  the  plasma  of  the  blood  is  not 
combined  but  free. 

Before  discussing  the  chemical  reaction  and  the  physiological  rela- 
tions of  the  combustion  of  glucose,  it  will  be  advantageous  to  consider 
first  the  formation  of  glycogen  and  fat  from  glucose,  the  relations  of 
glycogen  in  metabolism,  its  localization  in  the  tissues  and  to  discuss 
the  relations  of  the  combustion  of  sugar  to  the  glycogen  of  the  liver 
and  to  the  glycogen  of  the  extrahepatic  tissues.  Just  as  we  have  termed 
glycogen  the  proximate  storage  state  of  glucose,  and  fat  the  ultimate 
state  of  storage;  so  in  a  limited  sense,  we  may  term  the  hepatic  glycogen 
the  proximate  depot  of  glycogen,  and  the  muscular  and  other  extra- 
hepatic  glycogen  the  ultimate  depot  of  glycogen.  And  just  as,  in  a 
certain  sense,  fat  is  not  burned  in  the  body  until  the  glycogen  is  reduced 
to  a  certain  level,  so  the  ultimate  glycogen  is  not  converted  into  sugar 
until  the  hepatic  glycogen  is  reduced  to  a  certain  minimum. 

THE  FORMATION  OF  GLYCOGEN  AND  THE  ROLE  OF  GLYCOGEN 
IN    THE   CARBOHYDRATE   METABOLISM 

Glycogen  is  animal  starch,  a  polysaccharid  of  the  elementary  com- 
position C6Hio05,  of  large  but  unknown  molecular  weight.  In  water 
it  forms  a  colloidal  suspension,  not  a  true  solution;  the  glycogen  will 
not  diffuse  through  a  membrane,  offers  no  osmotic  pressure  of  measur- 
able degree,  does  not  conduct  the  electrical  current,  but  when  placed 
in  the  field  of  a  galvanic  current  migrates  to  the  anode.  Suspensions 
of  glycogen  rotate  the  plane  of  polarized  light  to  the  right,  but  do  not 
reduce  metals  in  alkaline  solution.  So  far  as  known,  the  glycogens 
of  the  different  parts  of  the  body  are  identical;  it  is  not  certain  that 
the  glycogens  of  different  species  are  identical.    Glycogen  exists  in  the 


248  METABOLISM 

body  only  within  cells  and  tissues,  never  suspended  in  the  circulating 
fluids.  The  blood  does  contain  glycogen,  but  only  within  the  leuko- 
cytes, not  in  the  plasma.  Within  cells,  the  glycogen  exists  in  the  proto- 
plasm in  amorphous  or  granular  state  as  free  glycogen;  and  secondly, 
in  combination  with  other  protoplasmic  constituents.  These  two 
states  we  may  denominate  free  (storage)  and  combined  glycogen. 
The  free  glycogen  may  be  recovered,  after  the  coagulation  of  the  pro- 
teins of  a  tissue,  by  prolonged  extraction  with  hot  water.  The  combined 
glycogen  can  be  recovered  only  after  digestion  of  the  protein  by  a  fer- 
ment like  trypsin.  The  free  glycogen  can  be  removed  from  an  organ 
or  animal  by  starvation,  work,  and  refrigeration.  The  combined  glyco- 
gen cannot  be  so  removed.  The  amount  of  free  glycogen  present  under 
ordinary  conditions  greatly  exceeds  the  amount  of  combined  glycogen. 
On  the  basis  of  calculations  of  analyses  of  the  tissues  of  the  dog,  the 
amount  of  combined  glycogen  in  an  average  human  body  may  be 
estimated  at  not  to  exceed  100  grams.  When  we  speak  of  a  glycogen- 
free  liver  or  other  organ,  this  refers  to  the  free  glycogen,  not  to  the 
combined  glycogen.  This  combined  glycogen  is  a  constituent  of  proto- 
plasm, combined  with  the  protein-lipoid  complex  of  which  protoplasm 
is  composed.  The  amounts  of  storage  glycogen  that  may  be  found  in 
the  body  are  varied  with  different  conditions  of  nutrition.  The  liver 
may  contain  from  a  few  grams  up  to  150  or  even  200  grams.  Muscle 
well  stocked  with  glycogen  may  contain  as  high  as  4  per  cent.,  the 
other  glands  of  the  body  quite  as  much.  Small  animals  have  been 
analyzed  to  contain  as  high  as  over  3  per  cent,  for  the  entire  body. 
For  a  man  of  70  kilos,  this  would  correspond  to  over  2  kilos  of  glycogen, 
or  2\  kilos  of  glucose,  adequate  fuel  for  the  body  for  five  days. 

The  formation  of  glycogen  from  glucose,  as  a  chemical  reaction, 
is  the  reversion  of  the  hydrolysis  whereby  glucose  is  formed  from 
glycogen  (glucose  +  water  =  glycogen),  it  is  the  reversion  to  the  state 
of  polysaccharid  from  the  primary  sugar.  An  intermediary  stage  must 
be  maltose.  So  far  as  we  can  observe,  the  formation  of  starch  in  the 
plant  and  of  glycogen  in  the  animal  are  quite  parallel  processes  in 
chemical  procedure  and  in  metabolic  meaning.  Upon  the  basis  of 
theory,  we  refer  this  reaction  to  the  activity  of  a  glycolytic  enzyme. 

The  glycogen  of  the  liver  is  derived  directly,  and  we  believe  under 
normal  conditions  solely,  from  the  diet.  This  statement  is  not  an 
actual  contradiction  of  the  fact  that  the  fetal  liver  contains  glycogen. 
The  direction  of  the  stream  of  migration  of  glycogen  seems  always  to 
be  centrifugal  from  the  liver.  The  liver  can  be  freed  of  its  glycogen 
(except,  of  course,  that  combined  in  the  protoplasm,  which  is  always 
excepted  from  this  discussion)  by  starvation,  especially  if  aided  by 
exercise.  Under  such  conditions,  the  body  contains  still  quite  large 
amounts  of  glycogen.  But  no  tendency  is  to  be  observed  for  this  to 
return  to  the  liver.  Thus  the  liver  which,  as  we  shall  later  describe, 
is  a  veritable  dumping  ground  for  fat,  receives  no  return  glycogen  from 
the  tissues  that  it  has  itself  enriched. 


FORMATION  OF  GLYCOGEN  IN  CARBOHYDRATE  METABOLISM  249 

The  liver  withdraws  the  excess  of  sugar  from  the  hyperglucemic 
blood  of  the  portal  vein  during  the  course  of  digestion  of  carbohydrate, 
converts  it  into  glycogen,  and  stores  it  in  the  protoplasm  of  the  hepatic 
cells.  Normally,  the  blood  of  the  hepatic  vein  contains  no  more  sugar 
than  0.1  per  cent.  So  far  as  our  analysis  goes,  the  blood  of  the  hepatic 
vein  contains  no  more  blood  than  does  the  venous  blood  that  it  meets 
in  the  inferior  cava.  Under  many  circumstances,  however,  there  must 
be  a  total  quantitative  difference  in  time,  since  under  conditions  of 
liberal  ingestion  of  carbohydrates,  the  blood  of  the  hepatic  vein  must 
contain  an  excess  of  sugar,  being  carried  to  the  muscles  for  conversion 
into  glycogen.  In  any  moment  of  analysis,  however,  this  is  too  small  to 
be  detected. 

The  Limit  of  Assimilation  of  Carbohydrates. — By  the  term  limit  of 
assimilation  of  carbohydrates  we  mean  the  amount  of  carbohydrate 
that  can  be  ingested  and  converted  into  glycogen  in  the  liver  without 
the  content  of  glucose  in  the  hepatic  vein  (that  is,  in  the  circulation), 
rising  materially  above  the  normal,  in  short  without  hyperglucemia. 
In  other  words,  the  limit  of  assimilation  of  carbohydrate  corresponds 
to  the  limit  in  time  of  the  glycogen-forming  function  of  the  liver.  If 
more  glucose  enters  the  liver  through  the  portal  vein,  in  the  unit  of  time, 
than  can  be  converted  into  glycogen  and  stored  in  the  liver,  then  hyper- 
glucemia will  result,  and,  of  course,  glucosuria.  There  is  no  limit  for 
starch  normally.  The  liver  can  always  handle  in  the  unit  of  time  all 
the  glucose  that  can  be  formed  in  the  process  of  digestion  from  any 
ingestion  of  starch.  For  the  disaccharids  and  for  the  three  mono- 
saccharids  (glucose,  fructose,  and  galactose),  the  limit  of  assimilation 
lies,  for  administration  in  simple  solution  on  the  empty  stomach,  from 
100  to  250  grams,  varying  with  different  individuals.  In  the  difference 
between  individuals,  100  to  250  grams,  are  included  two  variables — 
variation  in  powers  of  digestion,  and  variation  in  hepatic  function. 
The  difference  between  starch  and  sugar  is  merely  a  question  of  velocity 
of  absorption.  Two  hundred  grams  of  sugar  placed  in  the  duodenum, 
would  probably  be  resorbed  within  an  hour.  Two  hundred  grams  of 
starch  would  probably  not  be  digested  and  resorbed  within  five  or  six 
hours.  The  velocity  of  digestion  is  always  slower  than  the  normal 
velocity  of  glycogen  formation;  were  this  not  true,  alimentary  gluco- 
suria would  be  a  daily  occurrence. 

Formation  of  Glycogen  in  the  Liver. — From  what  constituents  of  the 
products  of  digestion  is  glycogen  formed  in  the  liver?  Only  from 
glucose,  and  therefore,  only  such  substances  as  are  capable  of  trans- 
formation into  glucose  can  be  regarded  as  builders  of  glycogen.  Per- 
fusion experiments  on  the  liver,  best  done  on  certain  toads,  have  indi- 
cated that  glycogen  can  be  formed  from  glucose,  fructose,  galactose, 
maltose,  glycerol,  and  formaldehyd;  from  cane  sugar,  milk  sugar,  and 
pentoses  no  glycogen  can  be  formed,  also  none  from  protein  (?).  The 
meaning  of  these  experimental  results  is  that  the  liver  is  able  to  split 
maltose   into   glucose;   convert  fructose   and   galactose  into   glucose; 


250  METABOLISM 

transform  glycerol  into  glucose  (through  the  stage  of  glycerose);  and 
like  plants  can  reduce  formaldehyd  to  glucose.  From  the  glucose 
thus  derived,  glycogen  is  formed.  Glycogen  is  not  formed  from  cane 
sugar,  milk  sugar,  and  pentose  because  the  liver  cannot  split  the  disac- 
charids  and  cannot  convert  the  pentose  into  hexose.  The  experimental 
results  in  the  case  of  amino-acids  are  contradictory.  For  though  the 
liver  does  not  show  an  increase  of  glycogen,  it  can  be  shown  to  display 
an  increase  of  sugar  when  certain  amino-acids  are  perfused  through  it. 
If  an  animal  made  glycogen-free  by  starvation  be  fed  on  a  pure  protein 
(like  casein)  in  excess  of  the  immediate  needs  of  the  body,  the  liver  will 
store  glycogen,  which  can  have  been  formed  only  from  the  amino-acids 
of  the  digested  casein,  via  glucose. 

Storage  Capacity  of  Liver  for  Glycogen. — To  what  variations  this 
assimilative  function  of  the  liver  is  subject,  is  not  well  known.  Like 
all  functions,  it  may  be  assumed  to  be  able  to  stand  an  overload;  like 
all  functions  it  must  be  susceptible  of  deterioration.  Experimentally 
it  can  be  reduced  or  abolished  by  the  medullary  puncture  of  Bernard. 
Apparently  there  is  in  the  medulla  oblongata  a  glycolytic  centre 
for  the  liver,  the  two  branches  of  the  arc  being  the  pneumogastric  and 
the  splanchnic  nerves.  The  splanchnic  nerves  must  be  the  path  of 
innervation,  since  the  puncture  does  not  produce  glucosuria  if  they 
are  severed;  but  it  does  succeed  if  the  vagi  are  cut,  and,  best  of  all,  if 
the  central  cut  ends  of  the  vagi  are  stimulated.  The  Bernard  puncture 
succeeds  in  small  animals,  birds,  and  reptiles;  and  the  facts  hold  infer- 
entially  for  man.  The  operation  is  followed  by  two  results;  the  liver 
is  made  free  of  glycogen  by  reason  of  the  conversion  of  its  stored  glyco- 
gen into  sugar;  and  hyperglucemia  results  from  this  excessive  transfer 
of  glucose  into  the  circulation  and  glucosuria  follows.  The  glucosuria 
endures  only  until  the  excess  of  sugar  is  removed  from  the  blood.  If 
the  liver  were  free  of  glycogen  before  the  puncture  was  done,  no  hyper- 
glucemia or  glucosuria  result.  If  now  sugar  be  administered,  it  will 
pass  without  hindrance  through  the  liver,  into  the  circulation  and 
out  of  the  kidneys.  The  same  result  will  be  obtained  if  sugar  be 
injected  into  a  branch  of  the  mesenteric  vein.  In  a  word,  the  only 
point  of  operation  is  the  stored  glycogen  of  the  liver;  if  there  be  no 
stored  glycogen,  there  is  no  result.  The  storage  capacity  for,  or  content 
of,  glycogen  in  the  muscles  or  the  other  tissues  is  in  nowise  disturbed. 
Even  if  the  liver  of  the  animal  receiving  the  puncture  be  filled  with 
glycogen,  no  hyperglucemia  or  glucosuria  will  occur  if  the  vessels  of 
the  liver  be  ligated.  The  operation  obliterates  the  storage  capacity 
of  the  liver  for  glycogen;  it  wipes  out  any  existing  deposition  and 
prevents  any  new  deposition. 

The  explanation  of  this  peculiar  phenomenon,  which  is  of  the  greatest 
interest  to  the  physiologist  but  lacks  entirely  the  importance  for  the 
understanding  of  diabetes  that  was  previously  ascribed  to  it,  is  not 
easy  to  give.  If  the  glycogen  stored  in  the  liver  were  assumed  to  lie 
there  in  some  state  of  combination,  the  simple  freeing  of  which  would 


FORMATION  OF  GLYCOGEN  IN  CARBOHYDRATE  METABOLISM  251 

set  it  loose  in  the  circulation,  an  explanation  might  be  sought  in  that 
direction.  But  that  is  not  to  be  considered.  The  explanation  most 
probably  lies  in  a  disturbance  of  the  relations  of  equilibrium  and  fer- 
ment action.  The  conversion  of  the  glycogen  into  glucose  is  an  act  of 
fermentation.  A  shifting  of  the  station  of  equilibrium  alone  it  cannot 
be,  since  with  the  hyperglucemia,  the  direction  of  the  reaction  ought 
to  be  shifted  toward  the  glycogen,  not  away  from  it.  The  assumption 
of  the  formation  of  an  excess  of  the  glycolytic  ferment  might,  without 
serious  contradiction,  explain  the  result.  From  the  standpoint  of 
the  modern  hypothesis  of  hormones,  an  explanation  might  also  be 
sought,  though  it  is  difficult  to  adjust  this  hypothesis  to  the  purely 
nervous  impulse.  This  could,  however,  account  for  the  formation  of  a 
large  excess  of  glycolytic  ferment,  through  whose  activity  the  glycogen 
would  be  hydrolyzed  to  glucose.  The  really  most  difficult  feature  of 
the  situation  lies  not  in  the  fact  that  the  glycogen  is  converted  into 
sugar  to  the  full  extent  of  the  contained  glycogen;  but  when  the  liver 
contains  little  glycogen  and  glucose  is  presented,  the  liver  is  prevented 
from  forming  glycogen  under  conditions  that  normally  would  be 
attended  by  a  rapid  formation  of  glycogen.  The  reaction  of  hydration  is 
accelerated  and  the  reaction  of  anhydration  is  prevented.  Of  course, 
if  one  were  to  assume  one  ferment  for  the  transfer  of  glucose  to  gly- 
cogen and  another  ferment  for  the  hydrolysis  of  glycogen  to  glucose, 
it  were  easy  to  say  that  the  Bernard  puncture  stimulates  the  formation 
of  the  hydrolyzing  ferment  and  inhibits  the  formation  of  the  synthetic 
ferment.    But  in  such  an  explanation  nothing  would  be  gained. 

In  some  cases  of  extreme  jaundice  the  storage  capacity  of  the  liver 
for  glycogen  is  lessened  or  destroyed.  In  many  instances  of  advanced 
organic  disease  of  the  liver  an  alimentary  fructosuria  is  present,  due 
to  the  inability  of  the  liver  to  convert  the  fructose  into  glucose.  In 
the  same  class  of  cases,  however,  the  liver  does  not  exhibit  any  loss 
of  the  power  of  converting  glucose  into  glycogen.  To  the  chemical 
point  of  view  this  is  simple.  The  two  are  totally  different  reactions, 
and  it  is  natural  that  the  functions,  though  accomplished  by  the  same 
organ,  should  be  separate.  It  simply  means  that  the  function  of  the 
conversion  of  fructose  into  glucose  and  the  function  of  the  conversion 
of  glucose  into  glycogen  are  not  interdependent.  Another  illustration 
of  this  fact  is  contained  in  the  experimental  observation  that  following 
extirpation  of  the  pancreas,  the  liver  cannot  form  glycogen  from  glucose 
but  can  convert  fructose  into  glucose. 

In  carbon  monoxid  intoxication  we  have  another  illustration  of  the 
disturbance  of  the  glycogen-storing  function  of  the  liver.  Just  as  is 
the  case  of  the  Bernard  puncture,  the  glycogen  of  the  liver  is  hydrolyzed 
to  sugar  and  the  circulation  flooded,  with  resulting  glucosuria. 

There  is  under  all  conditions  a  certain  antagonism  between  the  storage 
of  glycogen  and  fat  in  the  liver,  as  though  there  were  not  room  for  both. 
Whether  this  may  be  the  explanation  of  the  frequent  occurrence  of 
glucosuria  in  fatty  degenerations  of  the  liver  is  only  conjectural. 


252  METABOLISM 

The  maximum  storage  capacity  of  the  liver  may  be  set  at  from  150 
to  200  grams.  Now  since  the  total  sugar  needs  (as  fuel)  of  the  body 
not  engaged  in  hard  work  are  not  over  400  to  500  grams  per  day,  it  is 
clear  that  the  liver  could  handle  the  entire  input  and  from  its  store 
supply  the  fuel  glucose  of  the  whole  body.  Since  the  absorption  of 
food  is,  however,  not  usually  evenly  distributed  through  the  twenty- 
four  hours  of  the  day,  it  is  probable  that  such  is  not  commonly  the  case. 
Nevertheless,  individuals  who  consume  only  moderate  amounts  of  sugar 
per  day,  say  300  grams,  and  with  it  considerable  fat,  might  easily  hold 
in  the  liver  all  the  sugar  ingested,  pending  the  needs  of  the  body 
for  fuel.  In  other  words,  the  provision  for  proximate  storage  would  be 
sufficient  for  the  entire  metabolism  if  the  life  and  diet  of  the  individual 
were  arranged  to  that  end.  As  a  rule,  this  is  not  so,  and  the  liver  is 
unable  to  store  all  the  carbohydrate,  it  must  be  stored  in  the  depots 
of  ultimate  storage  of  carbohydrate,  in  the  muscular  system.  How 
is  this  transfer  accomplished  ? 

Transference  of  Glycogen. — The  blood  contains  no  glycogen  except 
in  the  leukocytes.  It  is  beyond  possibility  to  suppose  that  the  leuko- 
cytes transport  the  glycogen  of  the  liver  to  the  other  tissues  of  the 
body.  The  glycogen  must  be  carried  in  soluble  form.  There  is  but 
one  way  to  accomplish  this — by  the  reconversion  of  the  glycogen  into 
glucose.  It  is  apparent  from  this  that  we  may  assume  that  there  are 
four  levels  in  the  sugar  concentration  of  the  circulating  fluids.  The 
lowest  level  is  the  level  of  combustion;  the  second  level  is  that  of  the 
formation  of  glycogen  by  the  muscular  system;  the  third  level  is  the 
level  of  the  formation  of  fat  from  sugar;  the  highest  level  is  the  level 
of  renal  retention.  To  present  this  hypothesis  in  concrete  form,  let 
us  assume  arbitrary  figures  for  these  four  levels  of  glucose  in  the  blood, 
namely,  0.07,  0.08,  0.09,  and  0.1  per  cent.  When  the  body  is  upon  a 
minimal  diet,  with  just  enough  carbohydrate  absorbed  evenly  through 
the  day  to  maintain  the  body  heat,  the  glucose  concentration  in  the  blood 
would  stand  at  the  lowest  level,  0.07  per  cent.  If  the  carbohydrate  be 
absorbed  unevenly,  so  as  to  overtax  the  liver  at  times,  or  if  an  excess 
over  fuel  needs  be  ingested,  the  concentration  in  the  blood  would  rise 
to  the  second  level,  0.08  per  cent.  Thereupon  the  glycogen-forming 
function  of  the  muscles  would  become  operative.  These  would  store 
up  in  glycogen  the  glucose  that  passed  out  of  the  liver  in  excess  of  the 
concentration  on  the  lowest  level,  to  yield  it  for  fuel  as  needed.  If 
the  ingestion  of  carbohydrate  in  excess  of  the  fuel  needs  of  the  body 
were  long  continued  and  large  enough,  the  blood  concentration  of  the 
glucose  being  kept  up  to  0.08  per  cent.,  glycogen  would  be  formed  and 
stored  in  the  muscles  and  other  tissues  until  their  full  storage  capacity 
was  reached.  Then  the  blood  concentration  would  per  force  rise  higher, 
to  the  next  level  0.09  per  cent.  At  this  point  the  function  for  the 
formation  of  fat  from  sugar  would  become  operative,  and  the  concentra- 
tion of  the  sugar  in  the  blood  would  be  kept  down  below  the  renal  level 
of  0.1  per  cent,  by  the  formation  of  fat  from  the  excessive  sugar.    This 


FORMATION  OF  GLYCOGEN  IN  CARBOHYDRATE  METABOLISM   253 

is  a  function  of  wide  adaptation,  and  large  ingestions  of  carbohydrates 
may  be  tolerated  without  the  renal  level  being  attained.  It  is  possible 
to  inject  considerable  amounts  of  glucose  and  demonstrate  by  repeated 
analyses  of  the  blood  that  the  sugar  content  of  the  blood  is  high,  with- 
out the  production  of  glucosuria.  This  fact  is  not  an  argument  for  the 
binding  of  sugar  in  the  blood;  it  merely  indicates  that  the  conception 
of  threshold  value  must  not  be  interpreted  in  too  rigid  a  manner.  An 
enormous  single  ingestion  of  sugar  will  send  the  blood  concentration 
up  beyond  the  renal  level.  It  is  naturally  not  to  be  assumed  that  the 
hypothesis  predicates  the  application  of  this  scheme  rigidly,  it  is,  of 
course,  adaptive  and  fluctuating  and  there  is  overlapping;  but  the 
dynamic  point  of  view  is  illustrated.  The  thoughtful  reader  will  ask 
at  once  if  the  fact  that  the  diabetic,  who  has  hyperglucemia,  does  not 
build  glycogen  and  fat,  is  not  a  contradiction  of  this  scheme.  It  is 
not,  for  the  simple  fact  that  among  the  defects  of  the  diabetic  metab- 
olism are  the  more  or  less  marked  loss  of  the  functions  of  formation 
of  glycogen  and  fat  from  glucose.  One  occasionally  meets  with  a 
diabetic  who  exhibits  a  pathological  obesity,  an  illustration  of  the 
result  when  the  power  of  forming  fat  is  retained  in  the  diabetic  body 
with  hyperglucemia.  The  hypothesis  as  outlined  must  in  the  end 
rest  upon  the  broad  chemical  generalization  that  the  phenomena  under 
discussion  are  to  be  interpreted  as  expressions  of  mass  concentrations 
and  reaction  velocities. 

Glycogen  Content  in  Muscle. — The  glycogen  content  of  muscle  varies, 
of  course,  with  the  state  of  nutrition.  While  under  conditions  of 
forced  feeding  it  may  be  as  high  as  4  per  cent.,  it  is  usually  not  over 
half  that  figure.  In  other  words,  the  muscular  system  can  contain 
enough  glycogen  to  support  the  heat  of  the  body  for  five  days;  but 
as  a  rule  it  contains  not  more  than  enough  to  support  the  heat  of  the 
body  for  two  days.  This  fact  of  analysis  is  confirmed  by  observations 
of  the  respiratory  quotient,  which  for  a  few  days  in  starvation  dis- 
plays the  value  noted  in  the  combustion  of  sugar,  falling  thereafter 
to  that  related  to  the  combustion  of  fat  and  protein.  The  situation 
is,  of  course,  not  rigid;  there  is  some  overlapping,  by  which  we  mean 
that  some  fat  is  burned  before  the  glycogen  of  the  body  is  depleted. 
Glycogen  is  stored  in  both  the  voluntary  and  involuntary  muscles,  most 
in  the  former,  whose  much  greater  bulk  in  any  event  would  make 
them  outweigh  the  involuntary  muscles  in  importance.  When  the 
liver  content  of  glycogen  is  high,  glucose  passes  into  the  blood  of  the 
hepatic  vein  and  thence  into  the  general  circulation  in  excess  of  the 
heat  requirements  of  the  body,  there  occurs  a  slight  rise  in  the  glucose 
concentration  of  the  blood,  a  rise  to  the  second  plane  of  the  scheme 
enunciated.  Consequent,  thereupon,  a  slight  rise  in  the  glucose  con- 
centration occurs  within  the  muscle  cell,  and  this  we  must  regard  as 
the  moment  determining  the  formation  of  glycogen  there.  The  act  of 
formation  of  glycogen  from  glucose  we  regard  here,  as  in  the  liver,  as 
the  reversion  of  the  reaction  of  hydrolysis  whereby  glucose  is  formed 


254  METABOLISM 

from  glycogen.  The  glycogen  formed  within  the  muscle  cell  is  stored 
in  amorphous  or  granular  form.  There  must,  of  course,  be  variables 
in  this  function.  Lately,  we  have  learned  that  certain  dystrophic 
diseases  of  the  voluntary  muscles  are  associated  with  reductions  in 
the  output  of  creatinin,  which  we  regard  as  the  specific  end  product 
of  the  muscular  metabolism.  Whether  such  diseases  are  associated 
also  with  reduction  in  the  glycogenous  function  of  the  muscles  has  not 
been  determined,  though  it  is  clear  that  the  powers  of  combustion  are 
in  nowise  reduced.  Once  deposited  in  the  muscle  cell,  so  far  as  we 
know,  the  glycogen  is  not  disturbed  unless  a  fall  in  the  concentration 
of  glucose  within  the  cell  provokes  its  hydrolysis.  The  one  exception 
to  this  statement,  noted  in  diabetes,  will  be  discussed  under  that  head- 
ing. It  will  suffice  here  to  say  that  while  normally  hyperglucemia  is 
followed  by  the  maximum  storage  of  glycogen  in  the  muscle  cell,  this 
does  not  hold  in  diabetes.  But  of  other  known  outside  influences  the 
glycogen  of  the  muscle  is  free.  Thus  the  puncture  of  Bernard  has  no 
effect  upon  it,  and  no  chemical  substances  exert  any  influence  upon  it, 
so  far  as  we  know. 

Conversion  of  Glycogen  into  Glucose. — The  conversion  of  glycogen 
into  glucose,  both  in  the  liver  and  in  the  muscles,  is  dependent  upon 
the  accelerating  action  of  a  ferment,  termed  glycogenase.  This  fer- 
ment is  formed  in  the  hepatic  and  muscular  cells,  and  is  not  derived 
from  the  circulation.  The  blood  plasma  contains,  it  is  true,  a  glycolytic 
ferment;  but  the  glycolytic  functions  of  the  muscle  and  liver  are  not 
dependent  upon  their  blood  supply.  In  truth,  the  enzyme  of  the  blood 
is  probably  derived  by  diffusion  from  the  liver  and  muscles.  It  is  a 
so-called  soluble  ferment,  in  that  it  can  be  extracted  from  the  parent 
cells.  When  brought  into  contact  with  glycogen,  under  proper  condi- 
tions of  concentration,  reaction,  and  temperature  and  free  of  bacterial 
infection,  glucose  is  formed,  through  maltose  as  the  intermediary 
state.  Traces  of  dextrins  also  can  often  be  detected,  not  only  in  experi- 
ments with  the  isolated  ferment-extract  acting  upon  glycogen,  but 
also  in  experiments  with  aseptic  postmortem  digestion  of  the  liver 
and  muscles.  If  a  well-nourished  liver  or  muscle,  free  of  bacterial 
contamination,  be  allowed  to  lie,  it  undergoes  a  postmortem  digestion 
involving  the  protein,  fats,  and  glycogen,  due  to  the  action  of  its  own 
intracellular  ferments.  Following  such  a  postmortem  digestion,  glucose, 
with  traces  of  maltose  and  dextrins,  can  be  isolated,  and  the  glycogen 
content  demonstrated  to  have  fallen  proportionately.  Such  experi- 
ments may  be  conveniently  carried  out,  if  glycolysis  is  the  object  of 
the  test,  with  the  liver  and  muscle  of  the  mollusca. 

Combustion  of  Glycogen. — The  glycogen  of  the  muscle  is  available 
for  both  the  induced  and  the  forced  combustion,  the  autogenous  com- 
bustion of  basal  heat  production  and  the  combustion  of  muscular 
work.  It  disappears  in  the  resting,  starving  body;  it  disappears  in 
the  work  of  muscular  contractions.  The  glycogen  content  of  an  isolated 
muscle  can  be  shown  to  diminish  proportionately  to  the  intensity  and 


FORMATION  OF  GLYCOGEN  IN  CARBOHYDRATE  METABOLISM  255 

duration  of  the  contractions  caused  by  stimulation  of  its  nerve  by  an 
electrical 'current.  The  glycogen  content  of  the  two  hind  legs  of  a  frog 
may  be  contrasted,  the  one  being  made  to  contract  by  electrical  stimu- 
lation while  the  other  lies  quiet;  the  glycogen  content  of  the  resting  leg 
will  be  found  to  be  greater  than  that  of  the  exercised  leg.  When  a 
muscle  is  paralyzed,  by  section  of  its  motor  nerve,  glycogen  accumu- 
lates in  it.  If  the  peripheral  end  of  the  cut  nerve  be  stimulated,  the 
muscular  contractions  will  be  associated  with  the  disappearance  of 
this  glycogen.  Finally,  the  entire  body  of  an  animal  may  be  stocked 
with  glycogen  by  forced  feeding.  If  now  the  animal  be  worked  hard 
for  a  number  of  hours,  and  then  killed,  it  will  be  found  that  the  muscles 
are  very  poor  in  glycogen,  though  control  animals  demonstrate  that 
before  the  work  was  undertaken,  the  muscular  system  was  rich  in 
glycogen.  That  the  work  was  accomplished  on  the  combustion  of 
glycogen  (via  glucose,  of  course)  is  proved  by  the  fact  that  the  respira- 
tory quotient  during  such  an  experiment  is  found  to  be  high,  that  is,  to 
have  the  value  known  to  be  associated  with  the  combustion  of  sugar. 

It  is  possible  also  to  make  the  experiment  on  the  isolated  muscle 
by  contrasting  the  oxygen  and  carbon  dioxid  contents  of  the  arterial 
and  venous  blood  of  the  muscle.  The  resting  muscle  absorbs  some 
oxygen  and  gives  off  some  carbon  dioxid.  This  is  the  simple  heat 
production  of  the  muscle  acting  as  the  fire  box  of  the  body.  The  oxygen 
that  is  absorbed  is  often  in  excess  of  the  amount  of  carbon  dioxid  dis- 
charged by  the  resting  muscle.  If  the  muscle  be  stimulated  to  contrac- 
tions, both  the  absorption  of  oxygen  and  the  discharge  of  carbon  dioxid 
will  rise  rapidly,  the  later  often  disproportionately.  This  dispropor- 
tionate rise  in  the  CO2  output  during  muscular  work  may  in  a  certain 
sense  be  regarded  as  reciprocal  to  the  disproportionate  absorption  of 
oxygen  during  rest,  and  indicates  that  in  some  way  the  muscle  has  a 
capacity  to  bind  or  store  oxygen.  That  the  muscle,  on  contraction, 
can  give  off  carbon  dioxid  when  operating  without  circulation  in  a 
system  devoid  of  oxygen,  is  well  known;  and  possibly  this  carbon 
dioxid  represents  in  part  the  oxygen  that  was  stored  during  the  period 
of  rest.  On  the  other  hand,  as  will  be  elsewhere  noted,  carbon  dioxid 
can  be  derived  from  glucose  without  the  addition  of  oxygen. 

The  muscle  cells  possess  two  distinct  functions  of  combustion; 
combustion  in  the  state  of  rest;  and  combustion  for  the  support  of 
contraction,  an  instance  of  the  transformation  of  latent  energy  into 
work.  One  can  make  steam  for  heating  purposes,  or  one  can  utilize  it  in 
an  engine  for  the  purposes  of  mechanical  work.  So  does  the  body  burn 
sugar,  and  both  functions  are  localized  in  the  muscular  system,  though 
the  two  processes  are  quite  as  distinct  as  a  steam-heating  plant  and  a 
steam  engine.  The  combustion  for  the  maintenance  of  the  body  heat 
occurs,  however,  not  wholly  in  the  muscles.  There  are  active  combustions 
in  other  tissues,  notably  in  the  liver,  and  particularly  in  connection  with 
the  protein  catabolism.  But  the  burning  of  carbohydrates,  including  the 
sugar  derived  from  protein  (and  of  fats  possibly),  occurs  unquestionably 


256  METABOLISM 

in  largest  part  in  the  muscular  system.  As  fuel  for  this  resting  combus- 
tion for  the  maintenance  of  body  heat,  the  muscles  use  the  glucose  of 
the  circulating  blood,  not  their  stored  glycogen,  so  long  as  glucose  is 
available  in  the  blood.  The  loss  in  the  glucose  of  the  blood  is  replenished 
by  the  liver  through  the  conversion  of  its  stored  glycogen  into  glucose. 
Only  when  the  hepatic  glycogen  is  reduced  and  the  glucose  concentra- 
tion of  the  blood  lowered  to  a  minimum,  does  the  muscle  cell  convert 
its  own  glycogen  into  glucose  and  burn  it.  The  muscle  does  not 
return  glucose  to  the  circulation;  it  retains  it  and  burns  it.  When 
the  liver  is  ablated,  the  blood  content  of  glucose  sinks  to  almost 
nothing. 

When,  now,  with  the  liver  and  muscles  well  stocked  with  glycogen 
we  perform  muscular  work,  whence  is  the  sugar  for  the  work  derived, 
from  the  blood  or  from  the  contents  of  the  muscle  cells?  It  might 
be  supposed  that  the  modus  operandi  were  different  for  the  auto- 
genous combustion  of  sugar  and  for  that  associated  with  muscular 
contractions.  This  is,  however,  not  the  case;  the  combustion  asso- 
ciated with  muscular  contraction  are  also  supported  by  abstraction 
of  glucose  from  the  circulating  blood.  The  loss  in  the  blood  is  made 
good  by  the  conversion  of  glycogen  into  glucose  in  the  liver.  This 
proceeds,  in  the  course  of  prolonged  muscular  exertion,  until  the 
hepatic  stock  of  glycogen  is  reduced  to  traces,  then  the  muscle  cells 
convert  their  own  glycogen  into  glucose  and  utilize  it.  In  other 
words,  the  muscle  cells  respect  their  own  stored  glycogen  and  draw 
upon  the  glycogen  of  the  liver  for  fuel  so  long  as  this  lasts.  While 
the  glycogen  of  the  muscle  is  proximate  to  the  muscle  cells  in  the 
spatial  sense,  it  is  ultimate  to  them  in  the  physiological  sense.  This 
seems  to  be  especially  true  of  the  heart  muscle;  it  is  possible  in  direct 
experiment  with  the  isolated  heart  to  demonstrate  the  dependence 
of  its  contractions  upon  the  glucose  content  of  its  medium. 

That  the  body  can  burn  sugar  directly  from  the  act  of  digestion, 
in  other  words,  that  the  liver  allows  the  glucose  when  needed  to 
pass  into  the  general  circulation,  can  be  shown  in  experiment.  If  an 
animal  be  worked  and  starved  until  free  of  glycogen  in  the  practical 
sense,  it  will  maintain  its  heat  production  upon  the  combustion  of 
protein  and  fat,  and  this  will  be  indicated  in  the  respiratory  quotient, 
which  will  be  between  0.75  and  0.8.  Very  soon  after  the  ingestion 
of  carbohydrate  the  respiratory  quotient  will  rise  to  about  0.9, 
indicating  that  glucose  is  at  the  time  the  chief  fuel  of  the  body.  If 
the  animal  be  not  fed  again,  the  respiratory  quotient  will  fall,  in 
from  five  to  ten  hours,  depending  upon  the  amount  of  carbohydrate 
ingested,  to  the  starvation  quotient. 

If  an  animal,  glycogen-free  in  the  practical  sense,  be  fed  a  protein 
free  of  carbohydrate  (as  casein  or  codfish)  in  excess  of  the  needs  of 
the  body,  glycogen  will  be  stored  in  the  muscles  as  well  as  in  the 
liver.  It  has  been  inferred  that  the  liver  forms  the  glucose  from 
the  amino-acids  and  that  the  muscles  derive  it  from  the  liver.    But 


FORMATION  OF  GLYCOGEN  IN  CARBOHYDRATE  METABOLISM   257 

as  the  storage  in  the  muscles  appears  early  and  is  not  preceded  by 
a  noteworthy  storage  in  the  liver,  it  may  be  fair  to  question  whether 
the  muscles  as  well  as  the  liver  may  not  have  the  power  of  forming 
glucose  from  the  amino-acids.  The  respiratory  quotient  of  such 
an  animal,  temporarily  taken  from  the  diet,  will  be  low.  If  now 
the  animal  be  exercised,  the  quotient  will  rise,  showing  that  the 
muscular  contractions  were  associated  with  the  combustion  of  sugar 
that  in  the  state  of  glycogen  was  lying  in  the  resting  muscles,  while 
the  heat  of  the  resting  animal  was  being  maintained  by  the  combus- 
tion of  protein  and  fat. 

When  as  the  result  of  starvation,  exercise,  or  refrigeration  the 
glycogen  of  a  body  is  exhausted,  upon  what  is  the  production  of 
heat  and  the  maintenance  of  muscular  work  supported?  By  the 
combustion  of  protein  or  fat?  In  what  chemical  state  does  this 
combustion  occur? 

Muscular  Work  and  Protein  Diet. — It  is  certain  that  the  most  exten- 
sive work  can  be  preformed  on  a  pure  protein  diet,  a  diet  of  protein 
like  casein  that  contains  no  preformed  moiety  of  carbohydrate. 
But  it  seems  now  equally  certain  that  it  is  only  the  carbonous 
fraction  of  the  protein  molecule  which  supports  muscular  work.  It 
is  immaterial  here  whether  all  this  carbon  be  converted  into  sugar 
or  whether  some  of  the  fatty  acids  be  burned  direct,  this  fraction 
alone  supports  the  muscular  work.  The  oxidation  of  the  nitrog- 
enous fraction  does  not  occur  in  the  muscles,  but  in  the  liver  in 
large  part,  and  is  not  available  for  muscular  work.  Muscular  work 
on  a  protein  diet  is  still,  therefore,  work  performed  on  the  basis  of 
sugar  combustion.  Protein  and  glucose  both  yield  about  4  Calories 
of  heat  in  the  body;  but  while  all  the  4  Calories  in  glucose  are  avail- 
able for  the  support  of  muscular  work,  not  all  of  the  4  Calories  in 
protein  are  so  available.  This  will  be  elucidated  in  a  more  appro- 
priate place  later.  It  is  here  only  important  to  have  it  understood 
that  when  the  muscle  works  on  a  protein  fuel,  it  actually  works  on 
the  combustion  of  sugar  derived  from  the  protein. 

Muscular  Work  and  Fat  Diet.— Finally,  it  may  be  easily  shown  that 
muscular  work  can  be  supported  solely  by  the  combustion  of  fat, 
and  that  the  fat  thus  burned  yields  its  full  heat  value,  9.4  Calories 
per  gram,  to  muscular  work.  In  what  chemical  state  is  this  com- 
bustion of  fat  accomplished  for  the  maintenance  of  muscular  work? 
It  would  be  very  simple  if  we  could  assume  that  fat  were  burned  as 
sugar.  If  we  could  assume  that  fat,  like  glycogen,  is  simply  an  in- 
soluble state  of  storage,  and  that  like  glycogen  it  has  first  to  be  returned 
to  the  state  of  glucose  to  be  burned,  it  would  make  the  mechanism 
of  the  body  combustions  very  simple.  But  we  have  no  experimental 
evidence  that  this  is  true.  For  the  present  at  least  we  must  believe 
that  fat  is  burned  in  some  way  directly;  and  this  form  of  combustion, 
whatever  it  may  be,  occurs  in  the  muscle  cell  when  it  supports  the 
work  of  contraction, 
17 


258  METABOLISM 

What  has  been  said  of  the  full  caloric  value  of  protein  not  being 
available  for  muscular  work,  does  not  conflict  with  the  law  of  the  iso- 
dynamic  heat  value  of  the  foodstuffs.  For  heat  production,  protein, 
sugar,  and  fat  are  isodynamic;  for  muscular  work,  however,  while 
fat  and  sugar  are  isodynamic,  the  full  caloric  value  of  protein  is  not 
available.  It  will  be  well  to  recall  here  that  of  the  combustion  that 
occurs  during  muscular  exercise  in  excess  of  the  combustion  during 
rest,  only  from  20  to  at  most  35  per  cent,  is  converted  into  mechanical 
work,  the  balance  is  simply  dissipated  as  body  heat. 


THE    FORMATION    OF    FAT    FROM    GLUCOSE 

Fat  we  have  designated  as  the  ultimate  state  of  fuel  storage. 
When  the  deposition  of  glycogen  has  reached  a  high  plane,  the 
intensity  of  the  formation  of  glycogen  would  obviously  suffer  inhibi- 
tion. If  now  the  input  of  carbohydrate  be  maintained,  it  is  clear 
that  the  plane  of  glucose  concentration  in  the  blood  must  rise.  The 
plane  of  glucose  concentration  in  the  blood  upon  which  the  forma- 
tion of  fat  is  based,  is  the  highest  plane  normally  attained.  It  is 
just  below  that  of  the  limit  of  renal  retention,  and  if  the  ingestion  of 
carbohydrates  be  maintained,  fat  will  be  continuously  deposited 
and  the  body  thus  protected  against  hyperglucemia  and  glucosuria. 
There  is,  of  course,  a  limit  even  to  fat  formation,  though  it  is  often 
very  distant.  Nevertheless,  the  occurrence  of  glucosuria  so  fre- 
quently seen  in  the  very  obese  indicates  that  they  are  living  at  this 
limit;  and  a  slight  excess  of  carbohydrate  input  is  followed  by  gluco- 
suria because  the  storage  capacity  for  glycogen  being  fully  utilized 
and  the  storage  capacity  for  fat  being  nearly  completely  utilized, 
hyperglucemia  is  easily  produced.  This  is  all  the  more  true  since 
the  obese  person  usually  has  a  very  fatty  liver  and  the  presence  of 
much  fat,  even  in  the  healthy  liver,  is  inimical  to  the  glycogenetic 
function  of  that  organ.  It  must  not  be  understood  that  the  forma- 
tion of  fat  does  not  set  in  until  the  storage  of  glycogen  is  completed. 
The  situation  is  not  so  literal  as  that,  there  is  some  overlapping, 
some  fat  is  formed  before  the  tissues  are  surcharged  with  glycogen. 
But,  as  a  whole,  the  state  of  affairs  is  made  clear  in  the  statement 
that  the  ultimate  depots  of  storage  are  not  utilized  until  the  proximate 
depots  of  storage  are  filled. 

It  is  only  by  exclusion  that  we  can  arrive  at  any  idea  of  the  site 
of  the  formation  of  fat  from  glucose.  It  is  not  formed  in  the  muscles. 
When  the  muscle  cells  have  their  fill  of  glycogen,  they  refuse  glucose 
from  the  blood  stream;  they  do  not  accept  it  and  form  fat  from 
it.  This  excess  of  glucose  then  circulates.  For  a  long  time  it  was 
believed  that  in  the  liver  occurred  the  formation  of  fat  from  glucose. 
This  may  be  true  to  a  limited  and  localized  extent;  but  the  fat  of  the 
general  tissues  is  not  formed  in  the  liver.    It  is  quite  inconceivable 


THE  FORMATION  OF  FAT  FROM  GLUCOSE  259 

that  this  fat  should  be  formed  in  the  liver  and  then  transported  all 
over  the  body.  The  experimental  evidence  is  against  it;  whenever 
fat  wanders  it  seems  to  go  always  toward  the  liver,  and  not  from  the 
liver.  The  situation  is  the  converse  for  fat  and  sugar.  The  liver 
sends  sugar  out,  and  does  not  receive  it  from  the  circulation;  fat 
the  liver  does  not  send  out,  but  fat  the  liver  does  receive  from  the 
circulation.  The  site  of  the  formation  of  fat  is  probably  in  the  areolar 
and  connective  tissues — in  the  bone  marrow,  subcutaneous  areolar 
tissue,  in  the  connective  tissues  about  the  muscles,  under  the  serous 
membranes,  etc.  The  excess  of  the  sugar  is  carried  to  these  tissues, 
and  here  by  cellular  action  converted  into  fat.  Apparently  it  is 
merely  a  question  of  glucose  concentration;  this  is  the  moment  upon 
which  the  formation  of  fat  from  sugar  must  be  based.  The  function, 
of  course,  is  variable  in  different  individuals. 

To  this  rule  of  action  of  this  function  there  are  exceptions.  Pan- 
creatic diabetes,  typical  diabetes  in  man,  is  one.  The  diabetic 
organism  has  lost  in  part  the  power  of  forming  fat  from  sugar.  This 
is  all  the  more  striking  when  we  recall  that  on  the  basis  of  the  law 
of  mass  action,  the  hyperglucemia  should  lead  to  the  excessive  forma- 
tion of  fat.  Now  and  then  a  case  of  diabetes  is  seen,  in  which,  with 
loss  of  the  power  of  burning  sugar  and  the  consequent  presence  of 
hyperglucemia,  the  function  of  the  formation  of  fat  from  glucose 
is  retained;  such  diabetics  fatten  inordinately.  Later  they  may 
lose  the  function,  and  will  then  lose  the  fat.  If  the  diabetic  organism 
could  retain  the  power  of  forming  fat  from  sugar,  it  would,  in  this 
act,  after  a  fashion,  circumvent  the  defect  in  the  combustion  of 
sugar.  On  the  other  hand,  one  may  meet  with  occasional  individuals 
who  have  normally  almost  no  power  of  forming  fat,  or  what  is  equiva- 
lent in  result,  an  unlimited  power  of  burning  glucose.  The  combustion 
of  glucose  is  normally  restricted  to  the  heat  needed  to  maintain  body 
temperature  under  the  conditions  of  the  existing  dissipation  of  heat. 
But  in  these  occasional  individuals,  the  more  carbohydrate  they 
eat  the  more  they  burn,  the  mechanism  of  heat  dissipation  being 
operated  to  the  maximum.  The  ingested  sugar  must  in  these  cases 
be  burned,  if  resorbed,  since  there  is  no  glucosuria  and,  therefore, 
no  hyperglucemia.  Typical  instances  of  acute  exophthalmic  goitre 
seem  to  behave  in  the  same  way.  The  powers  of  digestion  do  not 
seem  to  be  equal  to  the  capacities  of  combustion,  the  more  eaten, 
up  to  the  limit  of  digestion,  the  more  burned.  It  is  not  the  place 
here  to  discuss  whether  this  be  cause  or  effect.  It  is  simply  neces- 
sary to  understand  that  on  the  one  hand  the  power  of  forming  fat 
from  glucose  may  be  lost  even  with  hyperglucemia;  and  on  the 
other  hand,  it  may  be  impossible  with  the  maximum  ingestion  of 
carbohydrates  to  achieve  the  formation  of  fat,  evidently  because 
the  slight  hyperglucemia  necessary  for  the  formation  of  fat  is  not 
attained. 


260  METABOLISM 

Chemical  Process. — Through  what  chemical  process  is  the  forma- 
tion of  fat  from  glucose  accomplished?  The  question  is  related 
solely  to  the  derivation  of  the  higher  fatty  acids  from  glucose;  the 
glycerol  is  another  matter,  since  the  body  can  and  does  produce  it 
independently.  It  is  known  in  plants  that  when  fat  is  formed  from 
sugar  and  sugar  from  fats  the  free  fatty  acids  are  transiently 
present.  If  an  animal  be  fed  a  known  constant  diet,  rich  in  carbo- 
hydrate, and  the  nitrogen  in  the  stools  and  urine,  and  the  carbon 
in  the  stools,  urine  and  expired  air  be  estimated,  the  exact  amount 
of  carbon  left  in  the  body  may  be  calculated.  And  although  it  is 
known  that  this  carbon  is  left  in  the  body  in  the  form  of  fat  (the 
experiment  deals  with  an  animal  stocked  with  glycogen)  no  trace 
is  left  of  the  mechanism  of  the  transformation.  To  form  one  mole- 
cule of  stearic  acid,  three  molecules  of  glucose  or  six  molecules  of 
glycerose  may  be  conceived  to  unite,  after  the  fashion  of  a  chain, 
connected  by  the  aldehyd  groups.  Reduction,  or  successive  oxida- 
tion and  reduction,  would  permit  the  stearic  acid  to  be  attained. 
Any  attempt  to  write  equations  by  which  we  might  be  led  from  the 
molecule  of  glucose  through  lower  fatty  acid  to  higher  fatty  acid, 
must  reckon  with  the  certain  fact  that  the  reaction  in  all  its  physio- 
logical reactions  is  known  to  be  an  isothermic  one,  the  heat  value 
of  the  fat  formed  is  the  same  as  the  heat  value  of  the  glucose.  Just 
so  in  the  combustion  of  fat;  the  full  heat  value  is  obtained,  which 
indicates  that  if  we  are  to  assume  that  the  fat  is  burned  via  sugar  any 
equation  that  we  may  write  must  check  with  this  observation.  If 
all  the  carbon  in  sugar  were  stated  in  terms  of  fat,  1  gram  of  glucose 
would  form  0.53  part  of  fat,  with  a  heat  value  of  4.8  Calories, 
much  higher  than  the  3.8  Calories  observed  for  the  sugar.  It  is 
clear  that  if  the  fat  formed  from  a  unit  of  glucose  is  to  have  the  same 
heat  value,  some  carbon  must  be  extruded  in  the  reaction.  This  was 
taken  into  account  in  one  of  the  oldest  formulations,  as  follows: 

Glucose  Lactic  acid  Stearic  acid 

9  C6Hi206  =  18  C3He03  =  2  Ci8H3602  +  18  C02. 

In  this  equation,  however,  the  heat  value  of  the  fat  formed  from 
1  gram  of  sugar  would  be  only  3  Calories.  If  we  were  to  write  the 
reaction  : 

Glucose  Lactic  acid  Stearic  acid 

18  C6H1206  =  36  C3H603  =  5  Ci8H3602  X  18  C02 

the  heat  value  of  the  fat  obtained  from  1  gram  of  glucose  would  be 
the  same  as  that  of  the  sugar.  But  what  is  the  use  of  such  equa- 
tions? They  teach  us  absolutely  nothing  of  the  actual  state  of  affairs. 
Comprehensible  qualitative  equations  will  be  advanced  under  the 
heading  of  the  Fat  Metabolism. 


THE  COMBUSTION  OF  GLUCOSE  261 


THE    COMBUSTION    OF    GLUCOSE 

When  1  gram  of  starch  is  burned  in  the  calorimeter  it  yields  4.2 
Calories  of  heat,  the  disaccharids  yield  3.95  and  glucose  3.75  Calories 
per  gram.  While  the  body  burns  the  carbohydrates  completely, 
and  the  values  for  the  calculation  of  heat  production  should  be  the 
same  in  theory,  in  practice  it  is  necessary  to  have  a  rounded  figure, 
all  the  more  because  it  can  be  shown  that  our  analyses  in  the  body 
obtain  nearer  the  theoretical  values  for  the  sugars  than  for  starch, 
because  the  sugars  are  more  completely  absorbed  than  starch  and 
because  the  usual  diet  contains  all  the  forms  of  carbohydrate.  The 
figure  4  Calories  per  gram  has  been  found  to  form  a  satisfactory 
basis  of  calculation.  Glucose  is  burned  completely  to  water  and 
carbon  dioxid,  and  all  carbohydrates  are  converted  into  glucose 
before  being  burned.    The  equation: 

C6Hi206  +  6  02  =  6  H20  +  6  C02 

illustrates  that  the  molecule  of  glucose  contains  enough  oxygen  to 
form  the  water;  needed  are  the  six  molecules  of  oxygen  to  combine 
with  the  carbon  to  form  the  six  molecules  of  carbon  dioxid.  Placed 
in  terms  of  weights,  1  gram  of  glucose  combines  with  1.066  grams 
of  oxygen  to  form  0.6  gram  of  water  and  1.066  grams  of  carbon 
dioxid,  with  the  liberation  of  3.75  Calories  of  heat.  Assuming  that 
the  carbon  dioxid  is  eliminated  as  rapidly  as  formed,  0.29  gram 
of  carbon  dioxid  eliminated  corresponds  to  1  Calorie  of  heat. 
This  reaction  occurs  in  large  part  in  the  muscular  system.  It  cer- 
tainly does  not  occur  to  a  demonstrable  extent  in  the  circulating 
fluids.  To  some  extent  it  does  occur  in  the  large  glands,. especially 
the  liver.  But  for  practical  purposes,  the  muscles  are  the  fire  box 
of  the  body.  In  the  reaction  as  written  stand  only  the  original  sub- 
stance and  the  final  end  products.  What  are  the  intermediary  stages 
in  the  reaction;  through  what  chemical  processes  is  the  molecule  of 
glucose  burned?  While  it  is  important  to  realize  that  this  question 
cannot  be  answered  now  with  definiteness,  it  is  equally  important 
that  we  make  attempt  to  answer  it,  and  to  define  our  knowledge 
relating  to  it.  The  glucose  may  be  burned  directly  or  indirectly, 
though  in  either  event  the  reaction  must  be  one  in  many  stages. 

Direct  Oxidation  of  Glucose. — The  direct  combustion  of  glucose,  so 
far  as  our  present  chemical  conceptions  go,  could  only  occur  through 
stages  that  would  involve  d-gluconic  acid,  d-glucuronic  acid,  d-sac- 
charic  acid  or  oxalic  acid.  Without  further  discussion  oxalic  acid 
may  be  ruled  out  of  consideration.  The  formulae  of  d-glucose  and 
of  the  other  three-named  substances  is  here  given: 


262  METABOLISM 

d-glucose  d-glucuronic  acid.  d-gluconic  acid.         d-saccharic  acid. 

COH  COH  COOH                   COOH 

HCOH  HCOH  HCOH  HCOH 

HOCH  HOCH  HOCH  HOCH 

HCOH  HCOH  HCOH  HCOH 

HCOH  HCOH  HCOH  HCOH 

CH2OH  COOH  CH2OH                 COOH 

From  these  equations  it  is  clear  that  even  these  could  be  but  the 
very  beginnings  of  an  oxidation. 

D-glucuronic  acid  exists  in  traces  in  normal  urine,  and  there  can 
be  no  doubt  that  it  is  derived  from  glucose.  It  appears  in  the  urine 
only  in  the  paired  state;  it  has  never  been  found  in  the  circulating 
fluids  or  tissues  in  the  free  state.  Substances  such  as  camphor, 
chloral,  and  thymotin-piperidid  are  eliminated  conjugated  with 
d-glucuronic  acid.  In  an  individual  with  normal  carbohydrate 
deposits,  the  ingestion  of  such  substances  is  followed  by  the  elimina- 
tion of  a  correspondingly  increased  amount  of  d-glucuronic  acid; 
if  administered  to  the  starving  animal  this  is  not  the  case.  A  dose 
of  thymotin-piperidid  that  would  be  lethal  to  a  starving  animal  is 
not  so  when  administered  to  an  animal  in  normal  nutrition,  because 
it  is  distoxication  by  conjugation  with  d-glucuronic  acid.  The 
question  really  at  issue  is  whether  the  d-glucuronic  acid  is  formed 
naturally  and  simply  seized  upon  by  the  substances  with  which  it 
conjugates;  or  whether  these  substances,  so  to  speak,  provoke  the 
formation  of  d-glucuronic  acid.  In  the  first  instance,  it  would  be 
termed  a  normal  intermediary  product  of  metabolism;  in  the  latter 
event  a  pathological  product.  The  occurrence  of  d-glucuronic  acid 
in  the  body  will  be  discussed  in  another  content.  There  is,  however, 
no  warrant  for  the  idea  that  the  total  combustion  of  glucose  could 
possibly  pass  through  the  stage  of  d-glucuronic  acid. 

D-gluconic  acid  is  easily  formed  from  glucose  by  oxidation  in  the 
laboratory,  and  bacteria  accomplish  the  addition  of  oxygen  also. 
The  body  burns  it  with  ease,  and  in  the  diabetic  it  acts  antagonistic 
to  the  acetone  complex.  It  has,  however,  never  been  demonstrated 
to  occur  in  the  animal  body,  d-saccharic  acid,  which  is  closely 
related  to  both  d-glucuronic  acid  and  d-gluconic  acid,  is  not  known 
to  occur  in  the  body.  When  administered,  it  is  burned,  like  the 
other  two  bodies  under  consideration.  When  a  rather  large  dose 
of  d-gluconic  acid  is  given  to  an  animal,  a  small  amount  of  d-saccharic 
acid  may  be  eliminated  in  the  urine.  The  fact  that  all  these  three 
substances  are  burned  in  the  diabetic  organism  as  well  as  in  the 
normal  need  not,  as  has  been  supposed,  throw  doubt  upon  the 
theory  that  glucose  is  burned  normally  through  such  stages;  the 
defect  in  the  diabetic  might  be  precisely  in  the  first  stage.     What 


THE  COMBUSTION  OF  GLUCOSE 


2G3 


does  throw  grave  doubt  upon  the  hypothesis  is  the  fact  that  these 
substances,  one  and  all,  are  not  revealed  and  do  not  behave  in  metab- 
olism in  such  a  way  as  to  warrant  the  assumption  that  the  normal 
combustion  of  sugar  proceeds  through  them.  Yet  the  question  must 
be  left  open. 

Indirect  Oxidation  of  Glucose. — The  most  likely  possibility  of  an 
indirect  oxidation  of  glucose  is  to  be  sought  in  the  reaction  of  alcoholic 
fermentation.  According  to  this  hypothesis,  glucose  is  first  converted 
into  lactic  acid,  this  then  splits  into  ethyl  alcohol,  precisely  as  in  the 
fermentation  with  zymase,  and  ethyl  alcohol  then  oxidized  through 
acetic  and  formic  acids  to  water  and  carbon  dioxid.    Thus: 


CHO 


HOH 


k 

I 
CHOH 

CHOH 

CHOH 


c. 


H2OH 


COOH 
CHOH 
CH2 

io  - 

CHOH 
CH2 


COH 

U 


COOH 
CHOH 


C02 


CH3 


CH2.OH 
CH3 


COH 

Ao 

CH3 


COOH 

I 
CHOH 

CH3 


C02 


CH2.OH 
CH3 


The  intermediary  equation  following  that  of  glucose  is  purely 
hypothetical,  the  next  is  methylglyoxal,  following  this  lactic  acid 
appears  and  from  this  ethyl  alcohol  and  carbon  dioxid.  The  intra- 
molecular alterations  in  the  hypothetical  substages  are  all  expres- 
sions of  successive  incorporations  and  extrusions  of  hydroxyl  and 
hydrogen  groups  to  accomplish  the  intramolecular  transformations. 
Lactic  acid  may  be  derived  from  acetol  through  methylglyoxal, 
so  that  this  step  is  not  hypothetical.  This  scheme  has  been  worked 
out  to  follow  the  line  of  least  resistance  in  the  transformation  in 
alcoholic  fermentation,  in  which  there  is  no  doubt  of  the  intermediary 
occurrence  of  lactic  acid  and  probably  of  methylglyoxal. 

What  have  we  for  data  bearing  upon  this  scheme?  That  bacteria 
and  plants  act  thus  upon  glucose  would  not,  of  course,  prove  that 
animals  do  so  burn  it.  Traces  of  ethyl  alcohol  are  always  to  be  found 
in  freshly  analyzed  muscles.  This  could  have  come  only  from  carbo- 
hydrate. Lactic  acid  also  is  to  be  found  in  fresh  muscle,  especially 
following  heavy  contractions;  and  it  occurs  also  in  the  autolysis  of 
muscle  in  such  large  amounts  as  to  make  the  derivation  there  only 
possible  from  sugar.  Lactic  acid  can,  of  course,  be  also  derived  from 
protein  (amino-acids).  But  the  more  the  matter  is  investigated,  the 
more  likely  it  appears  that  it  is  derived  in  the  muscle  from  glucose. 
When  the  muscle  works  with  little  or  no  oxygen,  lactic  acid  appears 
in  large  amounts,  an  observation  that  is  hardly  to  be  harmonized 
with  any  other  view  than  the  derivation  of  the  lactic  acid  from 
glucose.  Muscular  contraction,  under  normal  conditions  of  glucose 
concentration,  does  not  lead  to  any  exaggeration  in  the  nitrogenous 


264  METABOLISM 

catabolism  of  the  contracting  tissues,  which  is  difficult  to  harmonize 
with  the  appearance  of  lactic  acid  when  the  muscle  works  without 
full  supply  of  oxygen,  if  that  lactic  acid  be  held  derivable  from  the 
protein.  The  cleavage  of  glucose  to  lactic  acid  and  carbon  dioxid 
occurs  without  oxygen.  If  a  muscle  be  pumped  free  of  oxygen, 
placed  in  a  chamber  filled  with  nitrogen  and  stimulated  to  contrac- 
tions, carbon  dioxid  will  be  given  off  and  the  muscle  will  turn  acid 
from  lactic  acid.  This  is  perfectly  comprehensible,  according  to 
the  scheme  outlined  above.  The  demonstration  would  be  complete 
if  the  same  muscle  could  be  shown  to  contain  ethyl  alcohol,  but 
unfortunately  we  have  no  delicate  tests  for  traces  of  ethyl  alcohol. 

Direct  experiments  are  difficult  and  have  as  yet  not  given  un- 
equivocal results.  Sterile  extracts  and  precipitated  extracts  of 
muscle  and  other  animal  tissues  seem  able  to  form  a  certain  amount 
of  alcohol  and  carbon  dioxid  from  glucose.  In  other  words,  they 
contain  zymase.  But  the  results  quantitatively  are  not  satisfactory. 
If  an  extract  of  muscle  be  mixed  with  a  glucose  solution  of  known 
strength,  there  is  little  result.  If  now  a  pancreatic  extract,  which 
is  thermolabile,  be  added,  the  glucose  can  be  shown  rapidly  to 
diminish.  Expressing  such  an  experiment  in  the  language  of  the 
theory  of  catalysis,  we  would  say  that  the  muscle  contains  the  enzyme, 
the  pancreas  the  zymo-excitor.  The  relations  are  quite  the  same 
for  zymase.  The  expressed  ferment  of  the  yeast  is  able  to  ferment 
glucose  but  little  except  after  the  addition  of  a  solution  of  phosphate. 
Here  the  yeast  extract  contains  the  ferment,  the  phosphate  is  the 
zymo-excitor.  Under  the  conditions  of  the  tests,  it  has  not  been 
possible  to  demonstrate  the  presence  of  either  ethyl  alcohol  or  carbon 
dioxid.  Indeed,  recent  work  has  purported  to  show  that  the  glucose 
that  is  removed  has  been  simply  converted  into  isomaltose.  While 
in  work  of  this  kind  the  success  of  an  experiment  is  of  the  most  con- 
vincing influence,  failure  does  not  negate  the  hypothesis  for  the 
testing  of  which  the  experiment  was  undertaken.  The  correlation 
of  muscle  extract  and  pancreas  extract  is  so  harmonious  with  our 
experimental  knowledge  of  diabetes,  that  the  apparent  failure  of 
direct  fermentation  tests  should  not  be  taken  as  conclusive.  We 
know  that  when  the  pancreas  is  removed,  the  muscles  cannot  burn 
glucose  properly.  This  positive  fact  is  far  more  fundamental  than 
the  negative  result  of  test-tube  experiments  with  extracts  of  muscle 
and  pancreas.  The  action  of  the  internal  secretion  of  the  pancreas 
to  sugar  combustion  has  also  been  assumed  to  lie  in  a  relation  to 
the  passage  of  the  glucose  from  cells  to  blood  stream,  an  hypothesis 
intangible  and  far-fetched. 

Relationship  of  Pancreas. — The  relationship  of  the  pancreas  to  the 
metabolism  of  glucose  is  established  in  an  unequivocal  manner. 
There  exist  also  data  tending  to  show  that  the  thyroid  and  the 
adrenal  bodies  have  some  relation  to  the  sugar  metabolism.  While 
the  ablation  of  the  thyroid  body  does  not  cause  any  reduction  in 


THE  COMBUSTION  OF  GLUCOSE  265 

the  combustions  of  the  body,  the  hyperactivity  of  this  ductless  gland 
certainly  has  a  stimulating  action.  This  is  seen  markedly  in  acute 
exophthalmic  goitre,  in  which  the  combustions  of  the  body  (protein, 
fat,  and  sugar)  are  greatly  increased,  the  heat  production  of  the 
body  being  sometimes  doubled.  This  result  can  also  be  produced 
by  the  administration  of  desiccated  thyroid  glands  of  animals,  and 
upon  this  exaggeration  of  combustions  the  treatment  of  obesity  by 
thyroid  substance,  now  recognized  as  dangerous,  is  based.  This 
is  simply  a  clinical  fact,  for  it  we  have  no  explanation  that  rests 
upon  an  experimental  basis,  and  a  hypothetical  explanation  would 
scarcely  be  of  service.  Curiously,  direct  experiments  seem  to  show 
that  increased  thyroid  activity  operates  against  the  pancreatic 
stimulation  of  the  muscular  combustion  of  sugar.  In  such  direct 
experiments,  however,  the  relations  are  so  complicated  that  one  must 
exercise  the  greatest  care  in  the  interpretation  of  the  results.  Far 
more  important  is  the  clinical  fact  that  hypertrophy  of  the  thyroid 
body  is  associated  with  exaggeration  of  combustions,  and  following 
partial  extirpation  of  the  hypertrophied  thyroid  gland,  the  previous 
exaggeration  in  combustion  is  diminished. 

Relationship  of  Adrenal  Bodies. — That  the  adrenal  bodies  have  some 
relation  to  the  intestinal  secretion  of  the  pancreas,  is  certain.  How 
this  is  accomplished  is  not  understood.  That  it  has  any  relation  to 
the  so-called  internal  secretion  of  the  pancreas  is  not  clear.  Excision 
of  the  adrenal  bodies  nullifies  the  effects  of  the  Bernard  puncture. 
But  such  extirpation  must  effect  a  more  or  less  complete  section 
of  the  splanchnic  nerves,  which  are  the  efferent  paths  of  the  nervous 
impulses  concerned  in  the  effects  of  the  Bernard  puncture.  Chronic 
diseases  of  the  adrenal  bodies  may  be  associated  with  glucosuria. 
But  this  is  not  the  rule,  rather  the  exception,  certainly  for  tuberculosis 
of  the  adrenal  bodies.  At  present  there  is  too  much  confusion  and 
too  little  definiteness  for  inferences  to  be  reasonably  drawn.  The 
relation  of  the  internal  function  of  the  pancreas  to  the  mydriatic 
action  of  epinephrin  has  presented  a  new  point  of  view  in  the  problem 
of  interorganic  function;  but  an  interpretation  of  these  relations  is 
not  yet  at  hand. 

Combustion  without  Oxygen. — The  matter  of  combustion  without 
oxygen  merits  a  further  consideration.  The  phenomenon  holds  for 
wider  relations  of  life  than  the  isolated  muscle.  Many  worms  can 
be  kept  in  an  atmosphere  without  oxygen  for  days,  with  noteworthy 
movements.  A  frog  at  low  temperature  will  tolerate  an  oxygen- 
free  atmosphere  for  a  day.  In  such  instances  the  atmosphere  of 
the  experimental  chamber  contains  quite  a  little  carbon  dioxid. 
This  may  have  been  derived  in  part  from  oxygen,  which  as  we  have 
seen,  the  muscles  can  store.  In  addition  to  this,  the  cleavage  of 
glucose  into  ethyl  alcohol  and  carbon  dioxid  occurs  without  oxygen. 
It  is  possible  that  there  are  other  reactions  of  cleavage  that  either 
yield  oxygen  for  the  combustion  or  yield  C02  directly.     We  shall 


266  METABOLISM 

learn  later  that  the  reduction  of  diacetic  acid  yields  carbon  dioxid 
and  acetone,  and  CO2  is  thrown  off  when  taurin  is  formed  from 
cystin.  Not  much  heat  is  liberated  in  the  cleavage  of  glucose  to 
ethyl  alcohol  and  carbon  dioxid;  1  gram  of  glucose  splits  to  form 
0.511  gram  of  ethyl  alcohol  and  0.489  gram  of  carbon  dioxid  with 
the  liberation  of  only  0.3  Calorie  of  heat;  in  the  0.511  gram  of  ethyl 
alcohol  lies  the  remaining  3.5  Calories  of  heat. 

It  is  to  be  granted  that  the  proposition  that  all  the  sugar  of  the 
body  is  burned  through  ethyl  alcohol  is  striking,  and  rendered  none 
the  less  striking  when  the  physiological  action  of  alcohol  is  recalled. 
When  the  mass  relations  are  considered,  however,  particularly  in 
relation  to  the  fact  that  the  stage  of  alcohol  is  only  intermediate  and 
transitory,  the  wonder  disappears.  We  have  seen  that  the  resting 
man  burns  about  6  milligrams  of  glucose  per  second,  at  hard  work 
possibly  15  to  20.  This  would  correspond  to  from  3  to  10  milligrams 
of  alcohol  per  second,  or  from  250  to  800  grams  per  day.  Such  huge 
doses  of  alcohol  could  not  be  burned  if  ingested  by  the  mouth.  But 
this  is  the  result  of  concentration.  Generated  in  each  second  and 
distributed  throughout  the  entire  muscular  system,  appearing  only 
for  the  instant  as  an  intermediary  product,  it  is  clear  that  our  toxico- 
logical  conceptions  of  alcohol  cannot  be  applied  to  this  consideration. 
If  a  solution  of  glucose  be  infected  with  an  alcoholic  yeast  and  a 
vinegar  yeast,  and  permitted  a  free  supply  of  oxygen,  alcohol  will 
appear  only  as  a  transient  stage,  to  be  fermented  to  acetic  acid  as 
fast  as  it  is  formed  from  the  sugar.  So  in  the  body,  with  the  free 
supply  of  oxygen,  the  alcohol  would  be  burned  as  rapidly  as  formed. 
In  the  absence  of  oxygen  it  would  accumulate,  together  with  the 
lactic  acid,  and  doubtless  act  as  a  toxic  agent,  or  at  least  tend  to 
inhibit  the  reaction  to  which  it  was  due.  The  combustion  being 
regarded  as  localized  within  the  muscle  cells,  the  alcohol  would 
never  reach  the  circulation  or  the  nervous  system,  upon  which  its 
toxic  actions  are  displayed.  Since  the  combustions  proceed  evenly, 
and  since  the  amount  of  alcohol  to  be  recovered  from  fresh  muscles 
is  the  merest  trace,  it  is  evident  that  it  would  be  permissible  to  assume 
that  the  alcohol  would  be  burned  as  rapidly  as  formed.  Thus  the 
total  concentration  in  any  moment  could  never  be  over  20  milli- 
grams distributed  throughout  the  entire  muscular  system — a  con- 
centration that  could  not  in  the  wildest  stretch  of  imagination  be 
regarded  as  serving  to  cast  a  reflection  upon  the  credibility  or  admis- 
sibility of  the  theory  that  glucose  is  burned  in  the  body  through 
the  stage  of  ethyl  alcohol. 

Formation  of  Lactic  Acid. — Two  points  remain  to  be  considered 
in  this  connection.  The  formation  of  lactic  acid  from  glucose  is  a 
reversible  reaction.  In  some  severe  cases  of  diabetes,  the  administra- 
tion of  lactates  is  followed  by  increase  in  the  glucosuria,  the  sugar 
having  been  obviously  derived  from  the  ingested  lactic  acid  by  reversed 
reaction.     Experimentally,  this  holds  for  the  depancreatized  dog. 


THE  COMBUSTION  OF  GLUCOSE  267 

It  holds  also  in  the  animal  with  profound  phloridzin  intoxication, 
in  whom  ingested  lactic  acid  becomes  converted  into  glucose.  The 
two  experiments  are,  however,  absolutely  different  in  the  matter 
of  the  glucose  concentration  of  the  blood.  This  is  abnormally  high 
in  the  depancreatized  dog,  and  almost  nothing  in  the  phloridzinized 
dog;  yet  in  each  instance  glucose  is  formed  from  the  ingested  lactic 
acid.  We  have  said  that  when  ingested  in  the  normal  body,  lactic 
acid  is  burned;  probably  not  directly,  but  only  after  conversion  into 
sugar.  Lactic  acid  is  an  intermediary  stage  in  the  cleavage  of  sugar 
to  ethyl  alcohol,  according  to  that  theory  of  combustion.  An  excess 
of  lactic  acid  (such  as  would  occur  in  the  liver  following  ingestion 
by  mouth)  would  according  to  the  laws  of  general  chemistry  be 
expected  to  result  in  a  reversion  of  the  reaction  (formation  of  glucose), 
which  is  the  experimental  result.  Since  it  is  difficult  to  imagine  in 
what  other  way  than  through  ethyl  alcohol  lactic  acid  is  burned, 
these  observations  serve  to  strengthen  belief  in  the  correctness  of 
this  theory  of  combustion  of  glucose. 

The  cleavage  of  glucose  through  lactic  acid  into  ethyl  alcohol 
and  carbon  dioxid  is,  of  course,  only  a  cleavage,  exothermic  it  is 
true.  But  the  real  combustion  is  yet  to  occur.  This  we  believe  is 
accomplished  to  the  completed  stage  largely  in  the  muscles.  Oxida- 
tion ferments,  known  to  be  present,  carry  the  ethyl  alcohol  through 
acetic  acid  and  formic  acid,  in  fractional  stages,  to  the  end  products 
of  water  and  carbon  dioxid.  These  pass  into  the  venous  capillaries, 
and  this  conception  agrees  fully  with  the  fact  known  from  another 
quarter,  that  the  highest  concentrations  of  carbon  dioxid  known  in 
the  body  are  to  be  observed  in  the  muscle  tissue. 

Lactic  Acid. 

CH3 


i 


OH 

OOH 


Lactic  acid  occurs  in  the  body  under  many  different  circumstances 
and  of  different  derivations.  There  are,  however,  three  sources  that 
may  be  definitely  determined:  derivation  from  glucose,  from  amino- 
acids,  and  in  the  alimentary  tract  through  bacterial  action.  The 
lactic  acid  formed  in  the  alimentary  tract  is  held  to  have  been  derived 
from  carbohydrate. 

Lactic  acid  is  very  easily  burned  in  the  body.  The  lactic  acid 
that  is  formed  in  the  gastric  and  intestinal  fermentation  is  inactive. 
The  lactic  acid  that  is  formed  in  the  body  is  dextrorotary.  It  is 
doubtful  if  the  lactic  acid  of  normal  intestinal  fermentation  ever 
appears  beyond  the  hepatic  metabolism,  being  burned  instead.  It 
may  also  be  assumed  that  any  lactic  acid  normally  produced  in  metab- 
olism is  burned.  Whenever  we  encounter  it  as  a  metabolic  substance, 
it  has  either  escaped  combustion,  or,  in  fact,  its  very  formation  was  an 


268  METABOLISM 

abnormality.  For  all  practical  purposes,  whenever  it  appears  in  the 
blood  in  considerable  amounts  it  is  eliminated  in  the  urine.  When 
the  body  is  prevented  from  burning  it  the  kidneys  present  the  only 
avenue  of  elimination,  largely  as  ammonium  salt. 

Lactic  acid  is  present  in  the  intestinal  contents  of  normal  breast- 
fed infants.  It  is  contained  performed  in  mixed  diets.  It  is  to  some 
extent  formed  in  the  intestine  in  normal  digestion,  though  probably 
not  in  the  stomach.  Under  many  conditions  of  increased  bacterial 
activity,  large  amounts  are  formed  in  the  intestine.  In  the  stomach, 
also,  in  connection  with  chronic  gastritis,  atrophy  of  the  gastric  mucosa 
and  carcinoma,  especially  if  associated  with  pyloric  obstruction,  lactic 
acid  may  appear  and  in  very  large  amounts,  due,  of  course,  to  the 
action  of  bacteria  upon  carbohydrates.  While  lactic  acid  is  very  often 
present  in  the  gastric  contents  of  cases  of  gastric  carcinoma,  it  is  in 
nowise  pathognomonic  of  this  lesion.  The  lactic  acid  so  formed  is 
usually  entirely  burned  on  resorption.  But  in  a  few  reported  cases 
the  urine  has  contained  the  dextrorotatory  acid.  On  resorption  the 
levorotatory  form  is  apparently  converted  into  the  dextrorotatory 
form.  It  is  possible  that  the  presence  of  lactic  acid  in  the  urine  of  a 
case  of  gastric  carcinoma  might  be  interpreted  as  a  sign  of  organic 
hepatic  disease,  either  involvement  by  the  neoplasm  or  an  inflammatory 
or  degenerative  reaction. 

Lactic  acid  originating  within  the  metabolism  could  be  derived 
from  either  glucose  or  from  amino-acids.  In  birds  the  ingestion  of 
derivatives  of  lactic  acid  is  followed  by  the  formation  of  uric  acid.  It 
is,  however,  not  possible  to  assume  any  formation  of  lactic  acid  from 
purin  in  the  higher  organism.  In  theory  it  is  easy  to  derive  lactic 
acid  from  certain  amino-acids;  in  experiment  it  is  difficult.  The  equa- 
tions illustrate  the  possibilities  in  the  chemical  sense. 

Lactic  acid  Alanin  Serin  Cystein 

CH3  CH3  CH2.OH  CH2.SH 
CHOH  CHNH2  CHNH2  CHNH2 
COOH       COOH        COOH        COOH 

Other  possibilities  are  known,  such  as  the  formation  of  p-oxyphenyl 
lactic  acid  from  tyrosin.  But  when  these  possibilities  are  all  weighed, 
in  the  light  of  the  amounts  of  lactic  acid  formed  and  the  conditions 
under  which  it  occurs;  and  above  all  when  the  experimental  investiga- 
tions directed  to  the  elucidation  of  the  derivation  of  lactic  acid  under 
these  conditions  are  reviewed,  we  are  led  to  the  conclusion  that  as 
noted  physiologically  and  pathologically,  lactic  acid  is  usually  derived 
from  glucose. 

The  normal  blood,  muscles,  and  liver  contain  traces  of  it,  the  urine 
none.  In  the  presence  of  a  free  supply  of  oxygen  in  the  muscles  it  is 
quickly  oxidized;  in  the  absence  of  oxygen  it  accumulates.    It  is  present 


THE  COMBUSTION  OF  GLUCOSE  269 

in  notable  amounts  in  rigor  mortis,  and  is  developed  in  large  amounts 
in  autolysis.  It  is  possible  to  infer  that  it  passes  into  the  circulation 
only  when  the  conditions  of  combustion  in  the  muscle  are  unfavorable. 

Asphyxia  leads  to  the  accumulation  in  the  blood  and  tissues  of 
large  amounts  of  lactic  acid.  Dyspnea  has  the  same  result  if  long 
prolonged.  Intoxication  with  carbon  monoxid  achieves  the  same 
result,  in  an  obvious  indirect  manner.  It  is  also  seen  in  other  intoxica- 
tions, in  which  interference  with  the  processes  of  oxidation  is  more 
or  less  directly  observed,  thus:  hydrocyanic  acid,  amyl  nitrite,  cocain, 
arsenic,  phosphorus,  and  the  narcotic  anesthetics.  It  may  be  seen  in 
severe  essential  anemia. 

Diseases  of  the  liver  frequently  present  an  excess  of  lactic  acid  in 
the  blood  and  urine,  possibly  in  part  of  intestinal  derivation.  Thus 
cirrhosis,  fatty  degeneration,  acute  yellow  atrophy  of  the  liver.  It  is 
also  seen  in  eclampsia,  which  may  be  referred  to  the  liver.  In  severe 
instances  of  diseases  of  the  liver  the  elimination  of  large  amounts  of 
lactic  acid,  up  to  or  exceeding  20  grams  per  day,  amounts  to  a  veritable 
acidosis. 

There  is  no  excess  of  lactic  acid  in  diabetes.  On  the  contrary,  in 
some  cases  of  diabetes,  the  administration  of  lactic  acid  will  be  followed 
by  an  increase  in  the  glucosuria,  due  to  the  formation  of  glucose  from 
lactic  acid.  This  is  an  illustration  of  reversed  reaction,  lactic  acid 
being  normally  formed  from  glucose  in  the  cleavage  that  precedes 
its  direct  oxydation.  There  is  no  excess  of  lactic  acid  in  rachitis  and 
osteomalacia,  and  any  attempt  to  place  upon  lactic  acid,  directly  or 
indirectly,  the  responsibility  for  these  diseases  is  futile. 

Glucuronic  Acid. — In  the  discussion  of  the  modus  operandi  of  the 
combustion  of  sugar,  the  possibility  of  the  molecule  of  glucose  being 
burned  through  d-glucuronic  acid  was  stated,  but  the  conclusion  was 
reached  that  the  existing  data  do  not  tend  to  maintain  the  proposition. 
The  substance,  however,  is  a  constant  concomitant,  at  least,  of  the 
carbohydrate  metabolism;  and  its  qualities  in  certain  directions  are 
unquestionably  of  importance  to  the  organism. 

Glucuronic  acid  exists  in  the  body  in  the  state  of  conjugation,  in 
combinations  of  the  type  of  glucosids.  When  the  isolated  facts  are 
collected,  it  appears  that  the  number  of  substances  with  which  it  may 
be  conjugated  is  almost  unlimited.  On  analysis,  however,  it  will  be 
seen  that  they  are  all  either  alcohols  or  phenols.  Not  that  the  sub- 
stances entering  into  the  conjugations  were  either  alcohols  or  phenols 
originally,  but  in  the  body  they  undergo  conversion  into  alcohols  or 
phenols,  since  it  is  with  the  alcoholic  hydroxy  1  group  of  these  substances 
that  the  combination  occurs.  To  accomplish  this,  hydrocarbons  must 
be  hydroxylated,  as  must  be  also  members  of  the  heterocyclic  and  the 
hydro-aromatic  series.  Ketones  must  be  converted  into  secondary 
alcohols  and  aldehyds  into  primary  alcohols.  As  they  issue  from  the 
body,  therefore,  the  numerous  substances  that  conjugate  with  glucuronic 
acid  exist  in  the  state  of  alcohols  or  phenols.   Among  the  most  important 


270  METABOLISM 

of  these  substances  are  carbolic  acid,  camphor,  chloral,  phenacetin, 
acetanilin,  resorcin,  acetone,  menthol,  morphin,  and  pyramidon. 
Important  in  pathology  rather  than  in  toxicology  are  the  conjugations 
with  acetone  and  phenols. 

The  conjugations  of  glucuronic  acid  rotate  the  plane  of  polarized 
light  to  the  left;  the  free  acid,  however,  to  the  right.  The  substance 
has  marked  powers  of  reduction,  but  does  not  ferment  with  the  common 
yeast  germs.  It  can,  however,  be  fermented  to  1-xylose,  and  this  was 
previously  pointed  out  as  a  possible  source  of  derivation  of  pentose 
in  the  body.  It  is  present  in  the  blood,  in  tissues,  in  the  bile,  and  in  the 
urine. 

When  ingested  some  will  appear  as  conjugated  phenols  (the  ethereal 
sulphates  will  be  reduced),  some  may  appear  in  the  free  state  if  the 
ingestion  be  massive,  there  is  usually  much  oxalic  acid  formed,  and 
traces  of  gluconic  and  saccharic  acids  may  be  observed.  Glucosuria 
may  also  occur.  There  seems  under  all  circumstances,  physiological 
and  pathological,  to  be  a  mass  relation  between  glucuronic  and  sul- 
phuric acid  for  the  combination  with  the  aromatic  substances  resorbed 
from  the  intestine,  they  being,  so  to  speak,  contenders  for  these  aro- 
matic bodies.  If  either  one  be  held  constant  and  the  other  increased 
or  diminished,  the  division  of  the  aromatic  bodies  between  them  will 
be  varied  in  the  direction  of  highest  concentration.  This  is  one  reason 
why  the  estimation  of  the  ethereal  sulphates  in  the  urine  cannot  be 
employed  as  a  measurement  of  the  amount  of  aromatic  bodies  in  the 
urine. 

The  localization  of  the  conjugation  in  the  body  is  not  well  under- 
stood. Though  commonly  stated  to  occur  largely  in  the  liver,  there 
is  no  evidence  of  this,  unless  the  presence  of  glucuronates  in  the  bile  is 
to  be  accepted  as  such.  Since  different  extreme  organic  diseases  of  the 
liver  and  specific  intoxications  affecting  the  liver  do  not  result  in  any 
reduction  of  the  function,  a  localization  restricting  the  conjugation  to 
the  liver  is  very  improbable.  General  considerations  would  suggest 
the  muscles. 

Since  glucuronic  acid,  independent  of  the  diet,  is  always  to  be  found 
in  the  body  available  for  conjugation,  it  has  been  usually  inferred 
that  it  constitutes  a  normal  constituent  of  the  carbohydrate  metab- 
olism, the  product  of  a  side-reaction.  There  are,  however,  serious 
chemical  qualifications  to  this  view.  The  direct  oxidation  of  d-glucose 
to  d-glucuronic  acid  is  very  difficult  of  comprehension,  since  from  all 
we  know  of  the  molecule  of  glucose  the  aldehyd  group  (COH)  is  much 
more  easily  oxidated  than  is  the  primary  alcoholic  group  (CH2OH). 
But  in  glucuronic  acid  it  is  the  primary  alcoholic  group  and  not  the 
aldehyd  that  has  been  oxidized.  Under  these  circumstances  it  is 
much  more  logical,  chemically,  to  assume  that  the  glucose  combines 
with  the  alcohols  or  phenols  by  means  of  the  aldehyd  group;  this  being 
thus  protected  from  oxidation,  the  primary  alcoholic  group  under- 
goes oxidation,  with  the  production  of  the  conjugated  glucuronates. 


THE  COMBUSTION  OF  GLUCOSE  271 

In  other  words,  the  conjugations  occur  with  the  glucose,  not  with 
the  glucuronic  acid  preformed;  and  the  conjugated  glucose  is  then 
oxidized  to  a  conjugated  glucuronate.  Thus  the  amount  of  conjugated 
glucuronic  acid  is  really  a  function  of  the  amount  of  pairing  alcohols 
and  phenols,  if  the  glucose  concentration  be  normal.  Otherwise  we 
are  to  suppose  that  glucuronic  acid  is  formed  from  glucose,  and  if  the 
body  does  not  happen  to  contain  much  of  the  pairing  substances,  the 
excess  is  subject  to  further  oxidation.  This  is  contrary  to  observed 
facts. 

This  conception  of  the  situation  makes  far  more  intelligible  the 
distoxication  function  of  glucuronic  acid.  The  toxicity  of  the  alcohols 
and  phenols  when  conjugated  with  glucuronic  acid  is  practically  nil. 
A  certain  amount  of  the  aromatic  substances  formed  by  bacterial 
action  upon  the  end  products  of  protein  digestion  in  the  intestine  are 
regularly  conjugated  in  this  manner,  the  precise  amount  depending 
upon  the  mass  relations  with  sulphuric  acid  in  the  body.  When  any 
of  the  denominated  substances  are  ingested,  they  are  more  or  less 
completely   conjugated  and  thus  eliminated  in  an  innocuous  form. 

Glucuronic  acid  is  also  increased  in  certain  diseases.  Thus  in  pro- 
found jaundice;  in  some  cases  of  diabetes;  in  conditions  of  highly 
exaggerated  dyspnea  as  may  be  seen  in  diseases  of  the  lungs  and  heart; 
associated  with  multiple  fractures  of  the  bones  and  with  widespread 
traumatism  to  muscles;  in  starvation  and  sometimes  in  apparently 
normal  health,  excesses  of  glucuronic  acid  appear  in  the  urine.  Under 
these  circumstances  it  is  assumed  that  the  excess  is  not  provoked  by 
the  presence  of  any  pairing  body,  but  is  primary.  The  association 
with  muscular  traumatism  is  very  suggestive.  Such  primary  increase 
in  the  formation  of  glucuronic  acid  would  indicate  that  under  certain 
conditions  the  side-reaction  may  be  exaggerated.  Its  occurrence  in 
conditions  of  dyspnea  suggest  that  in  oxygen  hunger  such  exaggera- 
tion of  the  side-reaction  occurs.  The  increase  in  jaundice  may  be 
simply  a  resorption  with  the  bile.  The  occurrence  in  diabetes  and 
acidosis  has  been  frequently  misinterpreted.  It  ought  to  be  regarded 
here  as  a  provoked  glucuronuria,  due  to  the  presence  of  acetone  in  the 
blood,  acting  as  a  pairing  substance.  When  one  regards  the  chemical 
difficulties  attending  the  isolation  of  glucuronic  acid,  one  is  led  to  view 
the  reported  instances  of  primary  excess  of  the  substance  with  reserve. 
But  even  were  such  to  be  established,  it  would  give  no  warrant  for  the 
hypothesis  that  it  is  a  fundamental  stage  in  the  combustion  of  glucose, 
or  that  the  defect  of  diabetes  lies  in  the  failure  to  effect  oxidation 
at  this  point.  The  known  facts  do  not  warrant  any  definition  of 
glucuronuria  as  a  precursor  of  diabetes. 

In  practical  urinalysis  the  occurrence  of  glucuronic  acid  may  cause 
confusion  since  by  its  reactions  of  reduction  it  stimulates  glucose. 
But  it  is  easily  differentiated  by  examination  of  its  rotation  of  the 
plane  of  polarized  light,  its  resistance  to  fermentation  and  its  relations 
of  phenylhydrazin. 


272  METABOLISM 

Oxalic  Acid. 


COOH 
OOH 


A 


Oxalic  acid  is  present  in  traces  in  the  normal  tissues,  circulating 
fluids  and  the  urine,  and  may  be  present  in  the  urine  in  considerable 
amounts.  The  term  oxaluria,  as  usually  employed  by  the  physician, 
does  not  refer  to  the  amount  of  oxalic  acid  in  the  urine,  but  to  the 
amount  of  oxalate  crystals  that  the  urinary  sediment  contains.  There 
is  no  relation  between  the  content  in  oxalic  acid  and  the  sediment  of 
oxalates;  there  may  be  much  sediment  with  a  low  oxalic  acid  content; 
there  may  be  a  high  content  with  no  sediment  of  crystalline  oxalates. 
What  it  is  that  leads  to  the  formation  of  the  crystals  in  the  one  case 
and  the  solution  of  the  salts  in  the  other  case,  is  not  known.  The  cal- 
cium salt  is  the  most  insoluble,  the  magnesium  salt  is  quite  insoluble, 
the  potassium  and  sodium  salts  are  soluble.  Acidity  seems  to  increase 
solubility.  In  the  crystals  of  calcium  oxalate,  calcium  carbonate  is 
very  apt  to  be  occluded. 

Fruits  and  vegetables  contain  varying  amounts  of  oxalates.  These 
seem  to  be  resorbed  from  the  acid  stomach  and  the  upper  duodenum; 
from  the  neutral  or  alkaline  lower  intestine  there  is  little  absorption, 
as  the  salts  are  precipitated.  Thus  the  administration  of  acid  increases 
alimentary  oxaluria,  the  administration  of  alkali  reduces  it.  Of  the 
total  percentage  absorbed  from  the  food  under  even  known  conditions 
of  diet,  little  is  known.  This  inability  to  demarcate  the  exogenous 
oxalic  acid  makes  very  difficult  the  determination  of  endogenous  oxalic 
acid. 

Not  only  do  the  fruits  and  vegetables  contain  oxalic  acid,  but  it 
is  formed  by  fermentation  in  the  intestinal  tract.  The  amounts  so 
formed  are  not  known,  nor  have  pathological  variations  been  deter- 
mined. It  is  probable  that  bacteria  form  it  from  amino-acids  as  well 
as  from  carbohydrate;  it  does  not  seem  possible  to  restrict  it  by  control 
of  diet. 

For  the  endogenous  oxalic  acid  there  are  several  sources.  Reference 
has  already  been  made  to  its  derivation  from  glucuronic  acid.  Organ 
pulp  digested  with  glucuronic  acid  forms  oxalic  acid.  Traces  of  glyoxylic 
acid  may  be  found  in  the  urine,  which  might  have  been  derived  from 
the  cleavage  of  the  glucose  molecule  (methyl  glyoxal),  and  this  could, 
as  a  side-reaction,  give  rise  to  oxalic  acid. 

When  an  animal  is  placed  on  a  pure  protein  or  milk  diet,  oxaluria 
persists.  It  can  be  shown  that  the  administration  of  glycocoll  or  creatin 
will  result  in  increased  oxaluria.  This  is  the  explanation  of  the  large 
amounts  of  oxalic  acid  that  are  formed  following  the  ingestion  of 
gelatin  with  the  heavy  content  of  glycocoll.  Organ  pulp  digested  with 
glycocoll  yields  oxalic  acid.  In  a  way,  oxalic  acid  may  be  regarded 
as  the  end  product  of  the  oxidation  of  glycocoll  in  the  direct  sense, 


THE  COMBUSTION  OF  GLUCOSE  273 

though  it  is  certain  that  for  the  most  part  the  catabolism  of  glycocoll 
does  not  follow  this  route. 

Oxalic  acid  may  also  be  formed  in  the  test-tube  from  pyrimidin, 
purin,  ethylenglycol,  and  alloxan.  Digestion  of  purin  and  pyrimidin 
with  organ  pulp  also  yields  oxalic  acid.  But  it  is  very  doubtful  if  the 
purins  and  pyrimidins  in  the  body  are  to  be  regarded  as  sources  of 
oxalic  acid. 

The  fact  is  that  on  a  diet  free  of  oxalates,  the  oxalic  acid  of  the  urine 
is  but  the  merest  trace.  Thus,  whatever  the  chemical  or  experimental 
results,  it  is  clear  that  normally  but  little  oxalic  acid  is  formed  from 
amino-acids,  glucose  or  purins.  The  difficulty  in  the  interpretation 
of  increased  oxaluria  is  due  to  the  fact  on  the  one  side  that  we  cannot 
rule  out  the  formation  by  bacteria  within  the  alimentary  tract,  even 
though  we  could  control  the  input;  and  on  the  other  hand,  we  do  not 
know  just  to  what  extent  the  body  can  burn  absorbed  oxalic  acid. 
When  a  given  amount  is  ingested,  most  of  it  reappears  in  the  urine; 
but  since  the  unresorbed  fraction  cannot  be  measured,  we  do  not  know 
how  much  was  burned.  Of  injected  sodium  oxalate,  nearly  all  is 
promptly  eliminated  in  the  urine.  In  a  word,  we  lack  in  the  investiga- 
tion of  provoked  or  spontaneous  oxaluria  the  controls  that  alone  would 
enable  us  to  make  a  reliable  interpretation. 

Excessive  oxaluria  is  common  (whether  of  alimentary  or  endogenous 
origin  is  unknown)  and  of  vague  meaning.  Oxaluria  has  played  an 
active  though  supposititious  role  in  practical  medicine.  It  has  been 
widely  employed  as  a  convenient  receptacle  for  the  deposition  of  un- 
diagnosticated  cases  of  illness  of  all  kinds.  There  is  probably  an  idio- 
pathic oxaluria,  of  unknown  derivation,  a  metabolic  curiosity  at  present. 
There  is  no  known  relation  of  oxaluria  to  any  pathological  entity, 
within  the  intestinal  tract  or  in  the  metabolism. 

Oxaluric  acid,  a  combination  of  urea  and  oxalic  acid,  may  be  found 
in  traces  in  the  urine.  This  conjugation  occurs  so  easily  in  the  test- 
tube,  one  wonders  that  more  of  the  combination  does  not  occur  normally 
in  the  urine.     It  has  no  known  meaning. 

Glycerol. 

CH2OH 


HOH 
H2OH 


When  the  body  forms  the  higher  fatty  acids  from  glucose,  it  must 
also  synthesize  glycerol  to  combine  with  them  for  the  formation  of 
fat.  When  higher  fatty  acids  are  ingested,  they  are  resorbed  and 
at  once  combined  with  glycerol  to  form  fats,  and  this  glycerol  likewise 
must  have  been  synthesized  in  the  body. 

This  glycerol  may  have  been  derived  from  two  different  sources: 
from  glucose  and  from  amino-acids.    The  derivation  from  glucose  must 
occur  through  the  stage  of  lactic  acid,  according  to  present  conceptions. 
The  following  equations  illustrate  the  two  lines  of  possibilities. 
18 


274 


METABOLISM 


Lactic  acid 

COOH 
CHOH 
CH2 


Tartronic  acid 

COOH 

->        CHOH 

COOH 

Alanin 

CH3 

CH.NH2 

COOH 


Glyceric  acid 

COOH 
CHOH 
CH2OH 

Cystein 

CH2SH 

CH.NH2 

COOH 


Glycerose 

COH 
I 
CHOH      - 

CH2OH 

Serin 

CH2OH 

CH.NH2 

COOH 


Glycerol 

CH2OH 
CHOH 
CH2OH 


Cystein  after  deaminization  and  oxidation  would  yield  glyceric  acid ; 
serin  on  deaminization  would  yield  glyceric  acid;  alanin  would  yield 
lactic  acid. 

The  line  of  reaction  is  clear  in  the  series  of  carbohydrates.  For  the 
amino-acids,  the  direct  line  of  reaction  for  the  three  stated  amino- 
acids  is  not  clear,  but  the  general  configuration  is  such  as  to  make  it 
very  likely  that  glycerol  might  come  from  them  directly  as  well  as 
obviously  via  lactic  acid.  When,  however,  we  come  to  the  considera- 
tion of  the  amounts  ©f  glycerol  that  the  body  can  form  and  contrast 
these  figures  with  the  amounts  of  the  three  amino-acids  that  could 
be  formed  in  the  nitrogen  metabolism,  the  content  of  common  protein 
in  these  three  amino-acids  being  known,  it  is  clear  that  the  glycerol 
could  have  been  originated  only  from  glucose.  The  experimental 
investigations  have  led  to  the  same  result.  And  thus  we  feel  certain 
that  glycerol  in  the  body  is  a  derivative  of  glucose,  and  a  constituent 
of  the  carbohydrate  metabolism. 

When  glycerol  is  ingested  it  is  burned  (via  glucose),  unless  the  dosage 
is  excessive.  Then  some  may  appear  in  the  urine.  The  blood  con- 
tains normally  traces  of  glycerol,  which  are  tolerated  and  retained  by 
the  kidneys.  The  urine,  however,  occasionally  contains  traces  of 
glycerol  under  conditions  of  normal  metabolism.  It  occurs  as  a  by- 
product in  alcoholic  fermentation  (via  lactic  acid),  and  as  such  may 
be  present  in  the  normal  intestinal  contents.  When  ingested  in  huge 
doses  it  has  been  reported  as  increasing  the  output  of  uric  acid;  this 
might  be  taken  to  indicate  the  formation  of  tartronic  acid,  through 
lactic  acid;  from  this  dialuric  acid  could  be  derived,  and  from  this  uric 
acid,  as  in  birds.     The  experiments,  however,  are  not  convincing. 

The  intimate  relations  of  glycerol  to  the  glucose  metabolism  are 
indicated  in  several  ways.  When  glycerol  is  fed  to  the  depancreatized 
dog,  the  glucosuria  is  increased.  When  it  is  fed  to  the  phloridzinized 
dog,  the  glucosuria  is  increased.  When  it  is  perfused  through  the 
liver,  the  liver  content  of  glucose  and  glycogen  is  increased.  When 
glycerol  is  fed  to  the  diabetic  it  acts  just  as  sugar  does;  it  tends  to 
increase  the  glucosuria,  and  it  acts  antagonistically  to  the  acidosis. 
There  is  but  one  interpretation  of  these  several  results:  the  glycerol 
is  converted  into  glucose  via  lactic  acid.     And  conversely  to  this,  from 


THE  COMBUSTION  OF  GLUCOSE 


275 


glucose  through  lactic  acid  glycerol  is  formed.  It  is  important  that 
this  relationship  be  fully  realized.  When  glycerol  is  ingested  and 
burned,  it  is  in  reality  converted  into  glucose.  In  the  catabolism 
of  fat  the  glycerol  is  converted  into  glucose.  Possibly  one  of  the 
reasons  why  the  diabetic  organism  cannot  form  fat  properly  may  lie 
in  the  inability  of  the  body  to  form  glycerol  from  glucose. 

When  one  administers  higher  fatty  acids  they  are  converted  into 
neutral  fats  with  such  facility  that  one  is  almost  made  to  feel  as  though 
the  body  contained  stores  of  glycerol  ready  for  use.  The  facility  with 
which  glycerol  is  formed  when  needed  indicates  that,  like  ammonia  for 
protein,  it  is  a  normal  intermediary  stage  in  the  carbohydrate  metab- 
olism. It  may  be  assumed  that  wherever  there  is  lactic  acid  there  is 
also  glycerol  as  a  side  reaction.  When  there  are  fatty  acids  to  com- 
bine with  it,  it  is  thus  abstracted  from  the  carbohydrate  metabolism. 
Otherwise  it  exists  simply  as  a  side  reaction  within  the  main  stream 
of  the  glucose  metabolism.  When  fats  are  burned,  it  is  certain  that  the 
glycerol  derived  from  the  hydrolysis  of  the  neutral  fats  is  converted 
into  glucose.  The  discussion  as  to  the  convertibility  of  fats  into  sugar 
concerns  only  the  fatty  acid.  That  the  glycerol  fraction  is  converted 
into  glucose  has  long  been  known  and  recognized.  The  amounts 
involved  are  not  small.  From  the  glycerol  derived  from  the  cleavage 
of  1  gram  of  fat  not  less  than  one-eighth  gram  of  glucose  would  be 
formed. 

The  following  chart  indicates  the  metabolic  relations  of  glucose : 


Starch > — Glucose 


Maltose > — Glucose 


Cane  sugar— ► 


\ 


'Glucose 

Fructose 

i 
Glucose 


Milk 


y° 


lucose 


\ 


Galactose 

i 
Glucose 


G  lucose > — G  lucose 


< 

Glycogen 

Pentose 

- 

Galactose 

Glucosamin 

OS 

1 

| 

Glucothionic  acid 

1 

•2 

£ 
e 

Chondroitin 

i 

Glycerol 

o 

va 

03 
q 

Glucolipoid 

1 

Glucoprotein          t 

m 

< 

0 

/ 

//^ 

/      / 

Water 


Glucose         > — Lactic  acid 
Glycogen 

T 


Protein 


Ethyl  alcohol- 


276  METABOLISM 


GLUCOSURIA 

Under  the  term  melituria  are  included  all  the  different  conditions 
in  which  a  sugar  is  present  in  the  urine.  The  specifications  of  the 
chemical  nature  of  the  sugar  are  contained  in  the  term  maltosuria, 
saccharosuria,  lactosuria,  pentosuria,  fructosuria,  and  glucosuria.  With 
the  exception  of  glucosuria  all  these  forms  of  melituria  have  been 
described  under  the  sugars  concerned.  They  are  of  subordinate  interest, 
their  chief  importance  being,  in  fact,  as  well  as  in  theory,  their  rela- 
tions to  glucosuria  and  the  light  they  may  throw  upon  it.  Glucosuria 
is  a  condition  whose  meaning  is  so  fundamental  to  the  understanding 
of  the  carbohydrate  metabolism  as  to  warrant  an  extended  discussion 
of  the  facts  and  of  their  theoretical  interpretation. 

According  to  our  knowledge  of  the  relations  of  glucose  in  the 
body,  there  are  two  types  of  glucosuria:  hemic  and  renal  glucosuria. 
By  hemic  glucosuria  we  understand  the  elimination  of  glucose  in  the 
urine  because  of  excessive  concentration  of  glucose  in  the  blood;  by 
renal  glucosuria  we  understand  the  elimination  of  glucose  in  the  urine 
because  of  lowering  of  the  level  of  renal  retention.  In  hemic  glucosuria, 
the  height  of  the  impounded  waters  rises  above  the  floodgate;  in 
renal  glucosuria,  the  level  of  the  floodgate  is  lowered.  We  are  justified 
in  the  assumption  that  the  concentration  of  glucose  in  the  blood  and 
the  level  of  renal  retention  may  be  variable  in  time  in  the  same 
individual  in  health  and  in  disease,  and  from  individual  to  individual. 

Founded  upon  our  knowledge  of  the  relations  of  glucose  in  the  body, 
we  may  postulate  seven  ways  in  which  hyperglucemia  could  be  attained : 
(a)  By  excessive  ingestion  of  sugar,  ingestion  exceeding  in  time  the 
normal  function  of  glycogenesis  of  the  liver;  (6)  by  reduction  in  the 
function  of  glycogenesis  of  the  liver,  so  that  a  normal  input  cannot 
be  handled;  (c)  by  exaggeration  of  the  glycolytic  function  of  the  liver, 
glycogen  being  converted  into  glucose  in  excess  of  the  utilization  of 
it;  (d)  by  reduction  in  the  glycogenetic  functions  of  the  muscles,  or 
reduction  in  the  storage  capacity  for  glycogen  in  the  muscles;  (e) 
by  exaggeration  of  the  glycolytic  function  of  the  muscles,  glycogen 
being  converted  into  glucose  in  excess  of  combustion  and  returned  to 
the  circulation;  (/)  by  reduction  in  the  formation  of  fat  from  glucose; 
and  (g)  by  reduction  in  the  combustion  of  glucose  in  the  muscles. 
As  we  shall  see,  we  are  not  yet  certain  that  all  of  these  possibilities 
are  represented  in  experimental  or  clinical  instances  of  glucosuria. 
Nor  are  we  able  to  assign  every  case  of  glucosuria;  a  great  many  in 
fact,  we  are  unable  to  assign  to  any  definite  place  in  this  classification. 

The  lowering  of  the  level  of  renal  retention  is  a  process  that  is  local- 
ized in  the  kidney.  The  attempt  has  been  made  to  localize  this  in  the 
blood.  It  has  been  stated,  in  hypothesis,  that  the  kidney  retains 
combined  glucose  (glucose-lipoid,  glucose-protein,  colloidal  glucose  in 
short),  but  does  not  retain  free  glucose;  that  normally  the  retention 


GLUCOSURIA  277 

of  sugar  is  simply  an  expression  of  the  fact  that  all  the  sugar  of  the 
blood  is  combined  and  none  is  free.  When,  therefore,  glucose  appears 
in  the  urine  this  is  accepted  as  a  sign  that  there  is  free  sugar  in  the 
blood.  And  the  instances  of  glucosuria  due  to  the  lowering  of  the 
level  of  renal  retention  and  not  to  hyperglucemia  are  held  to  be  due  to 
the  abnormality  of  free  glucose  in  the  blood,  not  to  any  alteration  in 
the  renal  function.  Apart  from  the  fact  that  this  hypothesis  is  entirely 
unable  to  explain  glucosuria  with  hyperglucemia,  it  has  for  its  support 
no  conclusive  chemical  or  experimental  data,  and  has  against  it  the 
positive  physico-chemical  fact  that  by  far  the  larger  portion  of  the 
sugar  of  the  blood  is  in  the  free  state.  The  lowering  of  the  level  of 
renal  retention  is,  therefore,  to  be  regarded  as  a  process,  reaction,  or 
state  in  the  renal  structure.  When  we  recall  that  the  kidney  that 
normally  retains  colloids  entirely,  under  certain  conditions  of  disease 
eliminates  protein  in  such  a  way  as  to  exclude  physical  leakage,  we 
have  no  ground  for  wonder  that  under  conditions  of  disease  the  power 
of  retention  of  glucose  should  be  lowered  or  abolished.  Nor  is  it  to  be 
regarded  as  remarkable  that  the  kidney  should  be  able  to  retain  the 
glucose  below  a  certain  concentration  and  permit  it  to  pass  out  when 
above  that  concentration,  since  this  may  be  solely  a  question  of  the 
relation  of  osmotic  pressure  to  a  state  of  semipermeability.  We  come 
here  into  contact  with  the  difficult  question  of  the  modus  operandi 
of  secretion.  But  the  problem  does  not  bear  heavily  upon  our  concep- 
tion of  glucosuria.  When  we  know  why  and  how  the  kidney  secretes 
sodium  chlorid  and  urea,  it  will  be  time  to  take  up  the  question  why 
the  kidney  retains  glucose  below  a  certain  blood  concentration  and 
eliminates  it  above  that  concentration. 

Hemic  Glucosuria. — The  first  matter  to  be  determined  is  the  level 
of  renal  retention  of  glucose.  What  is  the  normal  glucose  content 
of  the  blood,  and  to  what  fluctuations  is  it  subject?  The  data  are  not 
extensive  and  trustworthy  enough  to  enable  us  to  give  a  precise  answer. 
It  is  not  easy  to  procure  the  amounts  of  blood  needed  for  careful  quanti- 
tative estimations ;  and  these  are  difficult  of  accurate  execution.  In  the 
past  the  tendency  of  the  figures  was  too  high.  The  figures  given  in 
the  arbitrary  scheme — varying  from  0.6  to  1  per  thousand — are  probably 
not  far  from  the  truth.  The  adjustment  is  usually  a  very  fine  one; 
but  this  need  not  be  true.  By  this  we  mean  that  usually  a  slight  in- 
crease will  cause  glucosuria.  It  is  doubtful  if  glucose  in  concentration 
of  over  one  part  in  the  thousand  should  be  termed  normal;  the  majority 
of  the  best  analyses  do  not  run  over  0.8  part  per  mille.  What  we  need 
are  not  haphazard  comparisons  from  individual  to  individual,  but 
repeated  analyses  on  one  individual  or  animal  to  determine  to  what 
extent  fluctuations  occur  in  the  glucose  concentrations  of  the  blood 
under  different  conditions  of  diet,  nutrition,  and  work. 

When  now  we  come  to  the  analyses  of  the  blood  of  individuals  with 
glucosuria  or  diabetes  or  of  depancreatized  dogs,  we  find  striking  con- 
tradictions, or  at  least  what  at  first  glance  strike  one  as  contradictions. 


278  METABOLISM 

While  one  usually  finds  the  highest  glucosuria  with  the  highest  hyper- 
glucemia,  one  may  find  pronounced  glucosuria  with  low  hyperglucemia, 
or  with  none;  and  one  may  find  striking  hyperglucemia  with  low  or  no 
glucosuria.  It  is  only  in  typical  rapid  diabetes  in  man  and  in  the 
diabetes  following  ablation  of  the  pancreas  in  animals  that  the  con- 
sistent concordance  of  high  hyperglucemia  and  high  glucosuria  is  to 
be  encountered. 

Reflection,  however,  makes  this  lack  of  apparent  concordance  clear. 
If  the  dam  impounding  the  waters  of  a  basin  be  a  broad  one,  the  water 
will  not  rise  much  above  the  level  of  the  dam,  because  the  wide  over- 
flow keeps  it  down.  If  the  kidneys  eliminate  the  excess  of  glucose, 
we  need  not  find  any  rise  in  the  concentration  of  glucose  in  the  blood. 
The  ingestion  of  a  large  amount  of  sodium  chlorid  will  be  followed  by 
the  rapid  elimination  of  the  salt  in  the  urine;  absorption  and  elimina- 
tion are  both  rapid.  But  one  would  not  find  the  conductivity  or  the 
depression  of  the  freezing  point  of  the  blood  increased  during  the  time 
of  the  experiment,  the  blood  would  not  contain  any  analytical  increase 
in  sodium  chlorid.  The  blood  passes  so  rapidly  through  the  cycle  of 
circulation  that  with  normal  action  on  the  part  of  the  kidneys  there 
is  no  retention,  no  rise  in  the  salt  level  of  the  blood.  The  same  is  true 
of  urea,  of  which  the  blood  contains  normally  the  merest  traces;  it 
may  be  ingested  in  large  amount,  without  the  urea  concentration  of 
the  blood  being  analytically  raised.  This  ought  theoretically  to  be 
the  normal  procedure.  So  soon  as  the  glucose  concentration  of  the 
blood  rises  to  the  level  of  renal  elimination,  this  elimination  should 
be  effective  enough  to  keep  the  blood  concentration  down  to  that 
level.  In  the  case  of  very  excessive  amounts  of  sugar  this  could  not 
be  expected  to  hold  true;  but  for  all  ordinary  cases  it  can  be  shown  that 
the  velocity  of  elimination  displayed  by  the  kidneys  ought  to  be  suffi- 
cient in  itself  to  prevent  any  material  rise  in  the  glucose  concentration 
of  the  blood.  Short  as  the  list  of  reliable  analyses  is,  they  are  enough 
to  teach  us  that  we  cannot  from  high  glucosuria  always  reason  to  high 
hyperglucemia. 

From  this  it  is  clear  that  the  relation  of  the  kidney  to  the  concentra- 
tion of  glucose  in  the  blood  need  not  be  constant  in  different  individuals 
and  in  the  same  individual  from  time  to  time.  The  variation  seems 
to  occur  always  to  the  side  of  lesser  elimination.  In  a  word,  the  kidney 
seems  to  get  accustomed  to  the  increased  concentration  of  glucose, 
the  elimination  is  restrained,  and  the  level  of  glucose  in  the  blood  rises 
more  and  more.  We  have  a  parallel  situation  in  the  case  of  uric  acid. 
The  elimination  of  uric  acid  in  the  normal  and  in  the  subject  of  chronic 
lead  poisoning  will  be  the  same;  but  the  blood  of  the  man  with  lead 
poisoning  will  contain  ten  times  as  much  uric  acid  as  is  to  be  found  in 
the  blood  normally.  The  attempt  to  raise  the  concentration  of  uric 
acid  in  the  blood  of  the  normal  man  will  fail,  because  the  kidneys  will 
eliminate  the  ingested  uric  acid  promptly,  which  they  will  not  do  in 
the  case  of  the  subject  of  lead  poisoning.     In  a  word,  the  kidney  in 


GLUCOSURIA  279 

lead  poisoning  is  tolerant,  insensitive  to  uric  acid,  the  level  of  elimina- 
tion has  been  raised — the  dam  has  been  built  up. 

From  this  it  must  be  borne  in  mind  that  what  we  really  mean  by 
hemic  glucosuria  is  not  glucosuria  with  analytical  hyperglucemia,  but 
glucosuria  associated  with  physiological  hyperglucemia  that  would 
become  analytical  hyperglucemia  if  the  renal  elimination  were  not 
effective.  The  adjustment  for  the  renal  elimination  is  usually  far  more 
fine  than  are  our  methods  of  analysis;  the  renal  elimination  may  keep 
the  glucose  content  down  to  within  the  normal  analytical  limits.  In 
alimentary  glucosuria,  so  far  as  we  know,  the  elimination  is  always 
effective,  the  blood  concentration  does  not  rise  materially.  But  in 
many  cases  of  diabetes  this  fine  adjustment  is  cut  out  of  operation  in 
some  way  unknown  to  us  yet,  the  renal  elimination  is  not  effective, 
and  the  concentration  of  glucose  in  the  blood  increases,  often  to  great 
height.  When  one  contemplates  the  figures  for  glucose  in  the  blood 
— 7  to  10  per  mille — and  contrasts  these  with  the  amounts  of  sugar  in 
the  blood  in  any  moment  of  time,  and,  finally,  with  the  amounts  of  sugar 
eliminated  in  the  urine  during  the  day,  one  is  indeed  led  to  realize 
how  poorly  sometimes  the  kidney  eliminates  the  sugar.  If  the  input 
of  carbohydrate  be  reduced  in  such  a  case,  the  amount  of  glucose 
eliminated  will  be  reduced,  but  the  concentration  in  the  blood  will 
remain  the  same.  Indeed,  it  may  be  possible  to  render  the  urine  free 
of  sugar,  while  the  blood  content  remains  analytically  much  above 
the  normal.  This  toleration  for  glucose  may  develop  very  gradually, 
as  has  been  observed  in  cases  of  simple  diabetes  that  were  getting 
worse ;  but  in  the  case  of  the  depancreatized  dog,  the  condition  develops 
simultaneously  with  the  glucosuria. 

Of  the  nature  of  this  modification  of  function  we  are  ignorant.  It 
is  not  possible  to  believe  that  it  rests  upon  any  anatomical  lesion  of 
the  kind  at  least  that  we  are  acquainted  with  in  the  kidney.  It  is  true 
that  many  advanced  cases  of  diabetes  have  renal  lesions;  but  early  in 
pancreatic  diabetes  in  dogs  there  are  no  renal  lesions  so  far  as  we 
know.  It  may  be  objected  that  possibly  there  are  renal  lesions  beyond 
the  horizon  of  present  histological  methods;  this,  even  in  the  face  of 
the  thousands  of  pages  that  have  been  written  in  description  of  the 
hundreds  of  thousands  of  sections  of  kidneys  that  have  been  cut,  will 
be  cheerfully  granted.  In  the  essential  sense,  structure  and  function 
may  be  assumed  to  go  together  in  these  matters.  It  is  possible  that 
exposure  to  high  concentration  of  glucose  may  so  affect  the  physico- 
chemical  constitution  of  the  protoplasm  as  to  render  the  semiperme- 
ability  to  glucose  less  effective.  And,  finally,  it  is  important  to  realize 
that  in  this  proposition  we  deal  with  a  hypothesis  directly  opposed 
to  that  upon  which  the  conception  of  renal  glucosuria  is  founded. 

If  a  discussion  of  the  clinical  and  experimental  occurrences  of  gluco- 
suria is  to  be  profitable,  we  must  make  the  attempt  to  determine  the 
type  to  which  the  particular  instance  belongs.  Otherwise  the  list 
becomes  simply  a  series  of  empirical  findings  of  glucose  in  the  urine. 


280  METABOLISM 

But  the  attempt  to  assign  the  clinical  and  experimental  instances  of 
glucosuria  to  groups  is  difficult  always,  and  often  impossible,  owing 
to  the  fact  that  we  have  so  few  analyses  of  the  glucose  content  of  the 
blood,  and  so  few  controls  of  or  experiments  with  the  diet.  The  inter- 
pretation of  much  of  the  clinical  data  is,  therefore,  for  the  present, 
clearly  provisional. 

(a)  Glucosuria  Due  to  Excessive  Ingestion  of  Carbohydrates,  Inges- 
tion Exceeding  the  Normal  Glycogenetic  Function  of  the  Liver. — This 
form  of  glucosuria  must  be  clearly  separated  from  the  melituria  due 
to  the  excessive  ingestion  of  diffusible  sugars  in  excess  of  the  diges- 
tive capacity  of  the  alimentary  tract.  In  true  alimentary  glucosuria 
an  amount  of  glucose  is  poured  into  the  portal  blood  in  excess  of  the 
normal  power  of  the  liver  to  convert  it  into  glycogen.  In  the  alimentary 
melituria,  sugar,  not  glucose,  is  absorbed  into  the  portal  circulation, 
which  sugar  must  be  in  the  liver  transformed  into  glucose;  if  the  liver 
cannot  do  this  at  all  or  if  the  amounts  to  be  so  transformed  are  in 
excess  of  the  powers  of  the  liver,  the  particular  sugar  will  appear  in  the 
urine. 

When  cane  sugar  is  ingested,  especially  in  large  amounts  and  upon 
the  empty  stomach  (from  100  to  250  grams  in  different  individuals) 
it  may  be  resorbed  in  small  part  unchanged.  This  resorbed  cane  sugar 
passes  through  the  liver,  which  has  no  power  to  split  it,  and  is  eliminated 
in  the  urine.  Sometimes  traces  of  fructose  and  glucose  also  appear 
in  the  urine,  due  to  the  fact  that  the  quantity  of  glucose  and  fructose 
passed  into  the  portal  circulation  as  the  result  of  the  digestive  cleavage 
of  the  cane  sugar,  was  in  excess  of  the  glycogenetic  power  of  the  liver. 

When  milk  sugar  is  ingested  in  large  amounts  (from  50  to  200  grams 
in  different  individuals),  especially  on  the  empty  stomach,  it  may  be 
resorbed  in  small  part  unchanged,  and  since  the  liver  has  no  power 
to  split  it,  it  will  be  eliminated  in  the  urine.  Glucose  will  very  rarely 
be  present  in  the  urine,  due  to  the  fact  that  the  digestion  of  milk  sugar 
is  relatively  slow  (slower  than  cane  sugar)  and  the  limit  of  the  glyco- 
genetic function  of  the  liver  is  not  so  easily  reached.  Theoretically, 
the  use  of  test  meals  of  cane  and  milk  sugar  for  the  purpose  of  deter- 
mining the  digestive  function,  the  power  of  splitting  the  sugars,  ought 
to  be  applicable;  but  practically,  there  is  no  data  bearing  upon  the 
question.  As  a  test  for  the  glycogenetic  function  of  the  liver,  however, 
cane  sugar  and  milk  sugar  ought  not  to  be  used,  glucose  itself  should 
be  employed. 

When  fructose  is  ingested  in  large  amounts  (in  from  100  to  200 
grams)  unaltered  fructose  may  appear  in  the  urine  in  traces;  if  the 
hepatic  function  of  conversion  of  fructose  into  glucose  be  reduced, 
fructose  will  appear  in  the  urine  in  large  amounts  and  over  a  prolonged 
period  of  time.  This  alimentary  fructosuria  is  a  test  of  great  value 
in  organic  diseases  of  the  liver,  as  elsewhere  detailed.  If  the  hepatic 
function  of  conversion  of  fructose  into  glucose  be  normal  and  the 
ingestion  be  very  heavy,  glucose  may  appear  in  the  urine,  with  possibly 


GLUCOSURIA  281 

traces  of  fructose.  The  fructose  reaction  is  a  test  for  a  specialized 
hepatic  function,  and  has  so  far  no  known  application  outside  of  that. 

The  test  meal  of  glucose  is  the  correct  test  for  true  alimentary  gluco- 
suria,  as  the  term  is  commonly  applied.  It  is  a  test  to  determine  the 
hepatic  function  of  glycogenesis.  Normal  individuals  will  tolerate 
from  100  to  200  grams  of  glucose,  taken  upon  the  empty  stomach, 
without  glucosuria. 

Melituria,  due  to  the  ingestion  of  excessive  amounts  of  sugars, 
amounts  in  excess  of  the  normal  powers  of  digestion  and  of  the  normal 
glycogenetic  function  of  the  liver,  is  relatively  common.  The  limit 
of  normal  hepatic  function  in  this  direction  seems  to  be  rather  low  in 
certain  individuals,  and  during  the  years  of  adolescence  and  with  sense- 
lessness in  diet,  such  meliturise  may  be  frequently  produced.  They 
are,  of  course,  easily  detected  and  excluded  by  supervision  of  the  diet. 
There  is  no  such  thing,  apparently,  as  glucosuria  following  the  inges- 
tion of  no  matter  how  much  starch  in  health;  the  normal  glycogenetic 
function  of  the  liver  is  superior  to  the  digestive  capacity  of  the  intestine 
for  starches.  Such  a  glucosuria  (glucosuria  ex  amylo)  is  always  abnor- 
mal, but  is  not  always,  as  was  long  believed,  diabetic.  In  theory  as 
well  as  in  fact,  there  is  no  reason  why  a  reduction  in  the  glycogenetic 
function  of  the  liver  below  the  plane  of  the  digestion  velocity  of  starches 
should  be  peculiar  to  diabetes. 

In  some  cases  of  alimentary  glucosuria,  this  occurs  only  when  the 
ingestion  of  carbohydrate  is  done  on  the  empty  stomach;  in  other 
cases  it  will  occur  when  the  carbohydrate  is  ingested  with  a  meal. 
In  some  cases,  the  elimination  of  glucose  continues  only  during  the 
period  of  time  occupied  in  digestion  (a  half  dozen  hours  after  the  meal) ; 
in  others  it  is  much  more  prolonged.  In  some  cases  work  during  the 
time  of  digestion  will  prevent  it;  in  others  not. 

An  easily  aroused  alimentary  glucosuria,  one  in  particular  that 
lasts  into  the  next  day  following  the  experiment  and  that  is  not  pre- 
vented by  work,  should  arouse  suspicions  of  a  masked  diabetes.  This 
rule  holds  of  course,  for  any  easily  aroused  glucosuria,  such  as  that  of 
fright  or  excitement.  In  such  individuals  the  limit  of  assimilation  of 
sugar  should  be  determined,  and  the  test  repeated  at  regular  intervals. 

(b)  Glucosuria  Due  to  Reduction  in  the  Normal  Glycogenetic  Function  of 
the  Liver. — Whenever,  in  a  body  whose  liver  is  poor  in  glycogen,  the  inges- 
tion of  a  normal  ration  of  carbohydrate  or  specifically  glucose,  is  fol- 
lowed by  a  glucosuria,  we  may  reasonably  assume  that  the  glycogenetic 
function  of  the  liver  is  reduced.  Such  a  state  of  affairs  need  not  lead 
to  more  than  a  transient  glucosuria,  if  the  combustion  of  sugar  and 
the  glycogenetic  functions  of  the  muscles  be  normal.  Otherwise  gluco- 
suria would  follow  every  meal  in  the  dog  with  an  Eck  fistula,  which 
is  not  the  case.  A  strictly  analogous  condition  is  the  fructosuria  of 
hepatic  disease,  in  which  the  hepatic  function  of  the  formation  of 
glucose  from  fructose  is  reduced.  Here  the  formation  of  glycogen  from 
glucose  is  reduced.    In  the  one  case  the  fructose  passes  into  the  general 


"2S'2  METABOLISM 

circulation;  in  the  other,  glucose.  These  conditions  may  be  classed 
under  the  term,  in  use  especially  in  France,  heptargia.  The  alleged 
reduction  in  the  toleration  of  sugar  in  pregnancy  requires  confirmation. 

Reduction  in  the  power  of  forming  glycogen  from  glucose  is  present 
in  all  severe  cases  of  diabetes.  Occasionally,  in  the  febrile  infections, 
in  pneumonia  and  influenza,  especially  in  exophthalmic  goitre,  in 
alcoholism  of  acute  type  and  in  lead  poisoning,  we  observe  instances 
of  glucosuria  following  the  administration  of  very  moderate  rations  of 
sugar.  Since  it  is  quite  certain  that  the  liver  in  these  conditions  is 
poor  in  glycogen,  it  seems  reasonable  to  regard  these  instances  of 
glucosuria  (which  may  even  be  glucosuria  ex  amylo)  as  due  to  reduc- 
tion in  the  glycogenetic  functions  of  the  liver. 

In  another  group  of  cases,  chronic  in  nature,  the  same  conditions 
are  noted;  in  exophthalmic  goitre,  in  gout,  obesity,  hypertrophic 
cirrhosis  of  the  liver,  in  fatty  liver,  chronic  alcoholism,  and  chronic 
fever.  It  is  clear  from  an  analysis  of  these  conditions,  that  it  is  not 
always  possible  to  rule  out  defective  glycolysis,  and  that  in  any  event, 
the  state  of  affairs  in  the  liver  is  different  in  the  different  conditions. 
In  some  it  is  possible  that  the  liver,  instead  of  being  poor  in  glycogen, 
is  overstocked  and  can  hold  no  more.  In  others,  the  liver  is  infiltrated 
with  fat  and  affected  with  fatty  degeneration,  conditions  in  which  the 
formation  of  glycogen  from  glucose  is  antagonized.  In  some  neither 
of  these  conditions  hold,  and  we  have  apparently  simply  a  reduction 
in  this  function  of  the  liver.  In  most  cases  of  profound  organic  disease 
of  the  liver,  the  function  of  glycogenesis  is  retained  in  a  most  remark- 
able manner.  In  fact  in  the  most  advanced  states  of  fatty  degenera- 
tion of  the  liver,  as  may  be  seen  in  pernicious  anemia  sometimes,  the 
function  is  normal.  It  is  usually  normal  in  jaundice.  In  organic  diseases 
of  the  liver  as  a  class,  this  function  of  the  liver  is  usually  retained  while 
the  function  of  conversion  of  fructose  into  glucose  is  usually  lost.  So 
far  as  gout  is  concerned,  it  is  most  often  in  gout  with  obesity  that  this 
glucosuria  is  met  with.  And  in  these  instances,  as  well  as  in  the  appar- 
ently simple  cases  of  obesity  in  which  it  is  encountered,  time  will  not 
infrequently  reveal  that  the  cases  were  masked  incipient  diabetes. 

There  is  supposed  to  be  a  certain  parallelism  between  glycogenesis 
and  the  distoxication  function  of  the  liver.  If  the  reactions  of  dis- 
toxication  were  all,  as  so  often,  reactions  with  the  formation  of  complex 
combinations  of  the  general  type  of  glucosids,  the  relation  to  glyco- 
genesis would  be  intelligible.  But  it  holds  also  for  distoxication  of  the 
metals,  which  are  combined  with  fractions  from  the  protein  and  not 
from  the  carbohydrate  group.  Diseased  liver  cells  that  have  lost 
in  part  their  power  of  converting  glucose  into  glycogen  are  often  the 
subject  of  more  or  less  extensive  fatty  degenerations,  and  these  may 
possibly  operate  against  the  protein  reactions  with  the  heavy  metals. 

Assuming  for  the  purpose  of  argument,  that  the  actual  state  of 
affairs  in  this  abnormality  consists  in  a  reduction  in  the  glycogenetic 
ferment,  the  above  presentation  assumes  further  that  this  is  due  to 


GLUCOSURIA  283 

disease  of  the  liver  cells  that  produce  this  ferment — just  as  hepatic 
fructosuria  is  supposedly  due  to  the  non-formation  of  the  transforma- 
tion ferment  on  account  of  disease  of  the  liver  cells.  But  it  is  possible 
that  the  modus  operandi  is  not  direct,  but  indirect.  Ablation  of  the 
pancreas  is  followed  promptly  by  reduction  in  the  glycogenetic  func- 
tion of  the  liver.  In  many  of  the  instances  cited  as  illustrations  of  this 
type  of  glucosuria,  it  is  certainly  an  open  question  if  we  are  not  dealing 
with  acute  or  chronic  disease  of  the  pancreas,  recoverable  in  nature, 
leading  to  a  certain  degree  and  for  a  certain  time  to  reduction  in  the 
glycogenesis  of  the  liver.  How  the  pancreas  brings  about  this  result  is 
not  known;  whether  by  repression  of  the  formation  of  the  glycogenetic 
ferment,  by  the  removal  of  some  condition  essential  to  the  action  of 
a  zymo-excitor,  or  by  excessive  glycolysis,  we  have  as  yet  no  idea. 

(c)  Glucosuria  Due  to  Exaggeration  of  the  Glycolytic  Function  of  the 
Liver. — This  is  a  very  common  type  of  glucosuria.  It  consists  in  the 
rapid  conversion  of  glycogen  into  glucose,  in  excess  of  the  combustion 
needs  of  the  body  and  in  excess  of  the  glycogenetic  function  of  the 
muscular  system.  There  is  no  doubt  that  when  the  liver  is  rapidly 
emptied  of  glycogen,  the  normal  glycogenetic  function  of  the  muscular 
system  is  easily  exceeded,  and  a  temporary  glucosuria  is  the  result. 
The  criterion  of  this  type  of  glucosuria  is  that  it  does  not  occur  follow- 
ing starvation,  hard  work  or  refrigeration;  in  other  words,  it  cannot 
occur  when  the  liver  is  poor  in  glycogen.  This  and  the  type  just 
described  are  opposites  in  this.  When  a  procedure  that  causes  gluco- 
suria by  exaggeration  of  hepatic  glycolysis  is  tried  in  an  animal  whose 
liver  is  poor  in  glycogen,  it  will  fail,  nor  will  glucosuria  occur  if  the 
animal  be  given  a  moderate  amount  of  sugar.  The  procedure  that 
causes  glucosuria  through  defective  hepatic  glycogenesis  will  not  cause 
glucosuria  in  a  temporarily  starving  animal  whose  liver  is  full  of  glycogen, 
but  will  do  so  in  an  animal  whose  liver  is  poor  in  glycogen,  following 
the  ingestion  of  a  normal  ration  of  sugar.  In  practice,  however,  it  is 
frequently  not  possible  to  classify  the  results,  as  glucosuria  occurs 
either  way,  i.  e.,  the  two  types  exist  in  the  same  individual. 

The  classical  illustration  of  this  type  of  glucosuria  is  to  be  found  in 
the  medullary  puncture  of  Bernard.  Many  forms  of  traumatism  of 
the  nervous  system  may  produce  this  glucosuria,  though  not  so  uni- 
formly. If  the  shock  or  stimulation  of  any  part  of  the  central  nervous 
system,  even  of  the  cervical  or  thoracic  sympathetic  ganglia,  be  pro- 
nounced enough,  it  acts  upon  the  glycogenetic  centre  just  as  the  actual 
puncture  would.  Of  disease  lesions  that  may  so  act,  we  may  mention 
tumors,  apoplexy,  concussion,  and  sclerosis.  In  some  of  the  chronic 
organic  diseases  of  the  nervous  system  intermittent  glucosuria  occurs, 
and  it  is  usually  to  be  classed  here.  In  some  of  these  instances,  how- 
ever, the  condition  is  dependent  upon  the  ingestion  of  carbohydrates, 
so  that  they  may  belong  to  the  type  just  previously  considered.  Func- 
tional conditions  of  the  nervous  system  may  also  bring  about  this 
glucosuria.     Thus  fright  or  extreme  excitement  of  any  kind  may  be 


284  METABOLISM 

associated  with  glucosuria;  of  this  the  glucosuria  seen  in  chained  or 
caged  wild  animals  is  an  illustration.  These  glucosuria?  are  all  transi- 
tory or  at  least  intermittent.  They  are  due  to  the  sudden  unloading 
of  the  hepatic  glycogen  in  the  form  of  glucose,  brought  about  we  believe 
by  a  sudden  excessive  formation,  or  at  least  action,  of  the  glycolytic 
ferment  of  the  liver. 

A  great  many  poisons,  that  in  large  doses  produce  glucosuria,  seem 
to  operate  by  action  upon  the  glycolytic  centre  in  the  medulla  oblongata. 
Strychnin,  which  produces  glucosuria  when  given  in  huge  doses,  does 
not  so  act  if  the  spinal  cord  be  cut  or  if  the  liver  be  removed  or  made 
free  of  glycogen.  Arsenic  apparently  tends  to  produce  glucosuria  in 
both  ways.  By  a  direct  action  upon  the  liver  cells,  it  depresses  the 
function  of  gly oogenesis;  by  its  action  upon  the  glycolytic  centre,  it 
tends  to  exaggerate  glycolysis  in  the  liver.  Morphin,  chloral  hydrate, 
amyl  nitrite,  cyanids,  nitrobenzol,  anilin,  antipyrin,  and  many  other 
drugs  in  large  doses  act  in  the  same  manner,  by  stimulation  of  the 
glycolytic  centre.  For  some  of  these,  the  question  of  an  internal 
asphyxia  may  be  properly  raised,  though  the  present  data  justify 
their  provisional  classification  here.  In  any  event,  the  matter  is  of 
lesser  importance,  since  it  has  been  shown  that  asphyxia  is  not  asso- 
ciated with  glucosuria  in  an  animal  whose  liver  is  free  of  glycogen. 

The  action  of  some  poisons  is  very  difficult  of  explanation.  In 
phosphorus  poisoning  the  liver  is  freed  of  its  glycogen,  without,  how- 
ever, either  hyperglucemia  or  glucosuria  occurring.  It  is  not  known 
what  becomes  of  the  glucose.  It  might  have  been  burned  in  excess. 
It  might  have  been  converted  into  fat  or  it  might  have  been  converted 
into  lactic  acid;  in  any  event  its  storage  in  the  muscles  in  the  form 
of  glycogen  is  excluded. 

Caffein  and  the  kindred  diuretics  may  produce  a  glucosuria  that 
is  related  to  the  unloading  of  glycogen  in  the  liver.  If  caffein  be  given 
as  a  diuretic  to  an  animal  poor  in  hepatic  glycogen,  no  glucosuria  will 
occur.  But  if  with  the  caffein  be  given  a  moderate  ration  of  sugar, 
glucosuria  may  occur.  Whether  this  can  be  due  entirely  to  disturb- 
ance in  the  glycogenetic  function  of  the  liver  is  questionable,  since 
the  glucosuria  is  proportional  more  to  the  diuresis  than  to  the  input  of 
sugar.  It  is  possible  that  we  have  here  an  illustration  of  a  slight,  transi- 
tory lowering  of  the  renal  level  of  the  blood  sugar,  an  illustration  of 
a  toxic  renal  glucosuria,  in  part  at  least. 

When  solutions  of  common  salt  of  certain  concentration  are  injected 
intravenously,  glucosuria  follows.  Since  glucosuria  does  not  occur 
after  section  of  the  splanchnic  nerves,  it  is  inferred  that  sodium  chlorid, 
like  the  poisons  mentioned,  acts  on  the  glycolytic  centre.  The  gluco- 
suria is  prevented  by  calcium  solutions,  and  this  fact  strengthens  the 
interpretation  given,  since  calcium  is  antitoxic  to  sodium  under  these 
circumstances  of  experimentation.  Some  of  the  investigations  have 
yielded  results  that  suggest  that  possibly  the  renal  permeability  to 
glucose  is  reduced  by  the  action  of  strong  saline  solutions.     In  the 


GLUCOSURIA  285 

absence  of  adequate  blood  analyses,  however,  this  suggestion  cannot 
be  properly  evaluated,  though  it  appears  to  be  reasonable. 

Exceeding  important,  in  fact  and  in  theory,  are  the  relations  of  the 
adrenal  bodies  to  the  sugar  metabolism.  There  are  great  experimental 
difficulties,  and  the  data  are  in  part  very  conflicting,  but  a  number 
of  certain  and  striking  facts  stand  out:  (a)  The  injection  of  epinephrin 
causes  in  the  normal  animal  glucosuria  and  hyperglucemia;  (b)  the 
ablation  of  the  adrenal  bodies  causes  hypoglucemia;  and  (c)  the  abla- 
tion of  the  adrenal  bodies  prevents  the  glucosuria  of  medullary  puncture. 

The  injection  of  large  doses  of  epinephrin  causes  glucosuria  not 
only  in  the  normal  animal,  in  the  animal  with  liver  filled  with  glycogen; 
it  causes  glucosuria  in  the  starving  animal  as  well,  not  so  pronounced 
in  amount  but  still  present.  It  does  not  cause  glucosuria  in  the  starving 
animal  following  the  action  of  phloridzin.  The  best  interpretation 
is  to  assume  that  epinephrin  stimulates  the  glycolytic  function  of  the 
liver  and  of  the  muscles  as  well.  When  the  body  has  been  well  drained 
of  glucose  through  the  combined  actions  of  the  combustions  and  phlorid- 
zin elimination,  epinephrin  loses  its  effect.  This  interpretation  is 
supported  by  the  observance  of  the  disappearance  of  muscle  glycogen 
following  the  use  of  epinephrin.  It  must,  however,  be  shown  that 
the  period  of  muscle  loss  of  glycogen  is  coincident  with  the  period  of 
hyperglucemia,  for  this  interpretation  to  stand.  The  idea  that  epine- 
phrin acts  as  a  depressor  to  the  internal  secretion  of  the  pancreas,  and 
thus  produces  glucosuria  in  an  indirect  way,  has  not  received  support 
in  the  latest  experimental  studies.  Epinephrin  is  probably  a  direct 
stimulant  to  glycolysis.  In  how  far  glycolysis  in  the  daily  functions 
of  the  organism  is  regulated  by  the  adrenal  bodies  is  entirely  unknown. 
The  glucosuria  of  epinephrin  is  in  no  way  an  expression  of  its  vaso- 
motor properties. 

The  ablation  of  the  adrenal  bodies  causes  hypoglucemia.  This 
is  very  difficult  of  explanation.  It  cannot  with  our  present  ideas  be 
conceived  as  operating  through  the  pancreas,  since  no  known  exaggera- 
tion of  pancreatic  action  can  cause  a  hypoglucemia.  There  is  no  excess 
of  combustion,  there  is  no  depletion  of  body  glucose  through  renal 
elimination.  All  that  seems  to  be  left  is  to  assume  that  the  station  of 
equilibrium  between  glucose  and  glycogen  (or  between  glucose  and 
fat)  has  been  shifted  away  from  glucose  and  toward  glycogen.  In 
other  words,  the  storage  of  glycogen  in  liver  and  muscle  is  increased 
at  the  expense  of  the  blood  concentration  of  glucose.  The  emotional 
glucosuria  of  animals  does  not  develop  after  adrenalectomy. 

Ablation  of  the  adrenal  bodies  prevents  glucosuria  after  the  Bernard 
puncture.  This  has  been  interpreted  to  mean  that  the  fibers  from 
the  glycolytic  centre  to  the  liver  run  via  the  sympathetic  nerves  through 
the  adrenal  bodies,  or  that  the  centre  operates  in  some  way  through  the 
mediation  of  the  adrenal  bodies.  No  interpretation  of  the  fact  is 
possible  with  the  present  data. 

Recent  experimental   researches  indicate  that   either  hypercapnia 


286  METABOLISM 

or  acapnia  may  be  followed  by  hyperglucemia  and  glucosuria.  Though 
the  mechanism  of  these  relations  is  not  yet  clear,  it  seems  probable 
that  some  of  the  diverse  clinical  forms  of  glucosuria  of  acute  type 
belong  to  the  one  or  other  of  these  conditions. 

Lastly,  the  glucosuria  of  diabetes  is  in  part  founded  upon  an  exaggera- 
tion of  hepatic  glycolysis  and  constitutes  one  of  the  metabolic  defects 
of  diabetes,  clinical  and  experimental. 

(d)  Glucosuria  Due  to  the  Reduction  of  the  Glycogenetic  Function 
of  the  Muscles,  or  Reduction  in  Their  Storage  Capacity  for  Glycogen. — 
Such  a  state  of  affairs  would  lead  to  hyperglucemia,  under  certain 
conditions  of  diet  and  hepatic  function  at  least,  and  thus  to  glucosuria. 
Such  a  state  of  affairs  exists  in  diabetes.  Beyond  this,  we  know  little. 
Some  of  the  facts  known  for  phosphorus  poisoning  could  be  reasonably 
interpreted  as  due  to  defective  muscular  glycogenesis.  It  is  possible 
that  some  such  thing  might  occur  in  the  muscular  dystrophies.  When 
the  motor  nerve  of  a  muscle  is  cut,  the  muscles  become  rich  in  glycogen. 
How  long  this  state  of  affairs  lasts,  whether  it  continues  during  the 
later  atrophic  degeneration  of  the  muscle  fiber,  is  not  known.  Muscle 
cells  in  chronic  neuromuscular  diseases  may  be  found  poor  in  glycogen; 
but  there  are  no  control  studies  to  indicate  that  this  may  not  have  had 
a  general  nutritional  foundation. 

(e)  Glucosuria  by  Exaggeration  of  the  Glycolytic  Functions  of  the 
Muscles. — This  would  result  in  sugar  being  returned  to  the  circulation, 
something  that  we  do  not  believe  ever  occurs  normally.  It  is  quite 
certain  that  it  occurs  in  diabetes,  else  how  can  we  understand  the  dis- 
appearance of  glycogen  from  the  muscles  in  acute  pancreatic  diabetes, 
when  the  body  burns  almost  no  sugar  and  there  is  pronounced  hyper- 
glucemia. It  means  a  shifting  in  the  equilibrium  glucose  < — ►  glycogen. 
Carbon  monoxid,  ether  and  chloroform  produce  glucosuria  in  the 
animal  whose  liver  is  free  of  glycogen  and  without  the  ingestion  of 
carbohydrate.  Since  in  these  instances  the  glucosuria  is  apparently 
due  to  hyperglucemia  and  not  to  any  lowering  of  the  renal  level,  unless 
the  sugar  can  be  derived  from  an  exaggeration  of  the  protein  catab- 
olism  (which  does  not  appear  to  exist)  there  seems  to  be  no  way  of  deriv- 
ing the  sugar  except  by  abstraction  from  the  stock  of  muscle  glycogen. 
It  is  not  to  be  inferred  that  the  action  of  these  intoxications  is  confined 
to  the  direction  here  under  consideration.  It  can  be  shown  that  ether 
and  chloroform  reduce  the  glycogenetic  function  of  the  liver.  And 
carbon  monoxid  produces  a  larger  glucosuria,  apparently,  with  the 
liver  stocked  with  glycogen  than  empty.  Carbon  monoxid  does  not 
act  through  simple  oxygen  hunger,  since  this  does  not  in  itself  lead  to 
glucosuria. 

(J)  Glucosuria  Due  to  Reduction  in  the  Formation  of  Fat  from  Sugar. 
— The  result  of  a  reduction  of  this  function  would  under  certain  condi- 
tions of  diet  lead  to  hyperglucemia.  It  occurs  in  diabetes  as  one  of 
the  defects  of  that  disease. 


GLUCOSURIA  287 

(g)  Glycosuria  Due  to  Reduction  in  the  Combustion  of  Glucose  in 
the  Muscles. — This  is  the  cardinal  defect  of  diabetes.  It  is  likely  that 
it  occurs,  to  some  extent  and  as  a  transient  condition,  outside  of 
diabetes.  It  is  possible  that  such  a  defect  is  produced  in  one  of  two 
ways;  either  the  muscle  ferment  is  defective  or  the  pancreatic  zymo- 
excitor  is  defective.  We  know  nothing  of  the  relations  of  the  muscle 
ferment.  We  know  that  ablation  of  the  pancreas  or  loss  of  its  function 
through  disease  leads  to  loss  of  the  power  of  burning  glucose  in  the 
muscles.  It  is  possible  that  acute  febrile  infections,  or  local  lesions  or 
infections  in  the  duodenum  or  bile  ducts,  might  lead  to  mild  inflamma- 
tory or  infectious  lesions  of  the  pancreas,  attended  with  partial  loss 
of  the  internal  function,  followed  by  recovery.  Possibly  some  of  the 
glucosuria  of  febrile  diseases  have  this  etiology.  It  is  clear  that  this 
hypothesis  might  also  explain  the  action  of  some  poisons  that  up  to 
the  present  have  been  considered  to  act  upon  the  liver  for  the  produc- 
tion of  glucosuria.    This  is  a  matter  for  controlled  future  investigation. 

Glucosuria  of  Unknown  Cause. — Leaving  aside  the  many  occasional 
findings  of  sugar  in  the  urine  without  determinable  causation,  there 
are  certain  quite  regular  types  that  must  be  mentioned.  One  of  these 
is  the  glucosuria  of  acromegaly,  due  probably  to  lesions  in  the  hypo- 
physis cerebri.  Another  is  the  singular  glucosuria  of  starvation  seen 
in  some  animals.  There  is  no  such  thing  as  a  starvation  diabetes  in 
man.  The  vagabond  glucosuria  that  was  once  regarded  as  such,  is 
probably  usually  due  to  chronic  alcoholism.  The  glucosuria  associated 
with  certain  diseases  of  the  skin  is  in  a  large  percentage  of  cases  a 
presenting  symptom  of  insidious,  so-called  latent,  diabetes.  The 
glucosuria  of  acid  intoxication  is  wholly  unclear.  The  glucosuria  of 
adolescence,  an  uncommon  but  undoubted  condition,  is  also  unclear, 
though  its  relations  to  vasomotor  variations  suggest  that  it  may  be 
of  renal  type.  Glucosuria  may  occur  in  connection  with  refrigeration, 
and  may  here  be  accompanied  by  lactic  acid  in  the  urine.  Refrigera- 
tion is,  of  course,  associated  with  excessive  combustion  of  sugar  and 
the  consequent  disappearance  of  glycogen.  Unless  the  cold,  like  shock, 
acts  upon  the  glycolytic  centre,  the  phenomenon  is  very  singular. 

Glucosuria  Due  to  Renal  Permeability. — In  all  the  instances  above 
considered,  glucosuria  is  due  to  hyperglucemia;  the  excess  of  blood 
glucose  simply  flows  over  the  renal  gate.  Under  true  renal  glucosuria 
we  understand  the  elimination  of  glucose  in  the  urine  in  the  absence 
of  hyperglucemia,  due  to  the  lowering  of  the  level  of  renal  retention 
of  glucose.  This  level  may  not  only  be  lowered,  it  may  be  practically 
abolished,  so  that  the  concentration  of  glucose  in  the  blood  becomes 
very  low.  The  classical  illustration  is  furnished  in  phloridzin  intoxica- 
tion. 

Phloridzin  is  a  glucosid  which  on  cleavage  yields  phloretin  and 
glucose.  When  injected  once  into  the  circulation,  glucosuria  appears 
within  a  short  time,  persists  for  a  number  of  hours  and  then  disappears. 
With  a  moderate  dosage,  the  glucose   concentration  of  the  blood  is 


288  METABOLISM 

not  lowered,  being  maintained  by  the  glycolytic  functions  of  the  liver 
and  muscles.  When  the  animal  is  starved  and  the  administration  of 
phloridzin  is  properly  proportioned  and  long  continued,  the  glucose 
concentration  of  the  blood  is  lowered,  sometimes  markedly. 

The  action  lies  in  the  kidney.  If  the  kidneys  be  extirpated  and  the 
animal  then  poisoned  with  phloridzin,  there  is  no  increase  in  the  blood 
concentration  of  glucose  above  that  of  the  control  animal.  In  birds, 
in  whom  the  kidney  is  very  resistant  to  hyperglucemia,  the  administra- 
tion of  phloridzin  is  promptly  followed  by  glucosuria.  Perfusion  of  the 
kidney  with  a  phloridzin-containing  blood  is  followed  by  the  elimina- 
tion of  glucose  in  the  secreted  urine.  When  phloridzin  is  injected  into 
one  renal  artery,  glucosuria  appears  first  on  that  side  and  on  the  other 
side  only  after  time  has  passed  for  the  glucosid  to  have  been  carried 
to  the  other  kidney  by  the  circulation.  The  action  of  phloridzin  is 
not  prevented  by  extirpation  of  the  liver,  while  it  lowers  the  hyper- 
glucemia produced  by  extirpation  of  the  pancreas. 

An  early  hypothesis  for  the  action  of  phloridzin  lay  in  its  cleavage. 
It  was  supposed  that  the  kidney  split  the  glucosid  into  the  two  compo- 
nent parts  and  eliminated  the  glucose  fraction.  The  phloretin  then 
continuing  in  the  circulation,  combined  with  another  molecule  of 
glucose  to  regenerate  the  molecule  of  phloridzin,  which  in  turn  was 
again  split  in  the  kidney  and  the  glucose  eliminated,  etc.  This  hypo- 
thesis failed  because  it  could  not  be  harmonized  with  the  facts.  It 
was  in  the  first  place  entirely  unclear  why  the  kidney  should  eliminate 
the  molecule  of  glucose  derived  from  the  postulated  cleavage  of  the 
phloridzin;  to  assume  a  secretory  defect  in  the  kidney  means  to  yield 
the  entire  argument.  Furthermore,  under  the  terms  of  this  hypo- 
thesis, a  molecule  of  phloretin  should  have  the  same  action  as  a  mole- 
cule of  phloridzin,  which  is  not  the  fact.  The  assumption  that  the 
kidney  splits  phloridzin  into  glucose  and  phloretin  is  not  supported 
by  experiments  with  renal  pulp.  The  curves  of  elimination  of  sugar 
under  controlled  and  varied  conditions  of  diet  are  entirely  against 
this  hypothesis. 

A  widely  supported  theory  attributes  to  the  phloridzin  the  power  of 
splitting  sugar  combinations  of  the  blood,  with  elimination  of  the 
freed  sugar.  The  hypothesis  runs  to  the  effect  that  the  kidney  retains 
only  bound  sugar,  not  free  sugar;  that  the  sugar  of  the  normal  serum 
is  bound  and  therefore  none  is  susceptible  to  renal  elimination.  In 
phloridzin  intoxication,  the  kidney  acquires  the  power  of  splitting  the 
sugar  combination,  setting  the  sugar  free,  when  the  normal  renal 
action  eliminates  it.  The  data  upon  the  basis  of  which  it  is  assumed 
that  the  larger  part  of  the  glucose  of  the  blood  is  bound  in  complex 
form,  is  not  chemically  trustworthy,  as  already  stated;  on  the  contrary, 
the  best  physico-chemical  investigations  lead  to  the  conviction  that 
the  larger  portion  of  the  sugar  of  the  blood  is  free.  There  is  some- 
thing rather  mystical  in  the  hypothesis  that  a  poison  bestows  upon 
a  tissue  a  specialized  function  that  it  does  not  normally  possess.    The 


GLUCOSURIA  289 

curves  of  glucose  elimination  under  the  influence  of  phloridzin,  with 
known  and  controlled  conditions  of  diet,  are  not  to  be  harmonized  with 
this  hypothesis.  The  fact  also  that  in  nephritis  and  in  the  sclerotic 
kidney  of  old  age,  phloridzin  has  little  power  to  produce  glucosuria, 
is  opposed  to  this  hypothesis. 

The  best  explanation  is  simply  to  say  that  the  phloridzin  abolishes 
or  reduced  the  property  of  the  kidney  to  restrain  glucose  from  elimina- 
tion, just  as  renal  lesions  reduce  the  power  of  the  kidney  to  effect  elimina- 
tion of  certain  substances.  In  each  instance  a  function  is  lowered; 
in  the  one  instance  a  retention  function  of  a  semipermeable  membrane 
is  lowered;  in  the  other  instance  an  elimination  function  of  a  semi- 
permeable membrane  is  lowered.  That  the  phloridzin  glucosuria  cannot 
be  exaggerated  by  diuretics  does  not  speak  against  this  interpretation. 
We  form  no  picture  of  this  defect  of  the  kidney;  future  investigation 
must  determine  that.  An  anatomical  defect  is  not  known;  nephritis 
and  albuminuria  are  not  produced  in  ordinary  phloridzin  intoxication, 
except  after  long-continued  and  excessive  administration. 

The  march  of  events  in  a  long-continued  intoxication  with  phloridzin 
is  very  instructive.  The  continued  elimination  of  the  glucose  in  the 
urine,  together  with  the  normal  combustion  of  glucose,  serve  to  reduce 
the  glucose  concentration  of  the  blood.  To  replace  the  loss,  the  liver 
converts  its  glycogen  into  glucose,  and  soon  becomes  free  of  glycogen. 
Thereupon  the  glycogen  of  the  muscles  maintains  the  combustions 
of  the  body.  The  elimination  of  sugar  continues.  Whether  this  sugar 
is  now  in  part  derived  from  the  glycogen  of  the  muscles,  returned  into 
the  circulation,  is  not  known,  though  it  has  been  usually  assumed  that 
this  is  the  case.  When  the  carbohydrates  of  the  body  are  reduced 
to  a  low  point,  the  body  falls  back  upon  the  combustion  of  fat  and 
protein.  From  the  amino-acids  of  the  protein  catabolism  glucose  is 
formed;  and  this,  too,  of  course,  falls  prey  to  elimination.  It  is  probable 
that  from  the  moment  the  hepatic  glycogen  is  exhausted  the  body 
maintains  its  combustion  upon  the  glycogen  of  the  muscles  so  long  as 
it  lasts,  and  the  sugar  of  the  urine  represents,  therefore,  sugar  formed 
from  protein  solely.  It  is  difficult  to  prove  this ;  but  if  this  interpreta- 
tion were  to  be  adopted,  we  would  be  spared  the  assumption  that  the 
glycogen  of  the  muscles  after  conversion  into  sugar,  instead  of  being 
entirely  burned  there,  is  in  part  returned  to  the  circulation.  When  the 
glycogen  of  the  muscles  is  low  or  exhausted,  then  the  body  is  entirely 
dependent  upon  fat  and  protein.  Both  are  burned,  in  different  propor- 
tions in  different  animals.  In  different  specimens  of  urine  from  different 
dogs,  the  glucose :  nitrogen  ratio  may  vary  from  4.4  to  2.8  : 1.  These 
represent  partly  the  ratios  of  utilization  of  fat  and  protein  in  different 
animals,  in  part  the  different  ratios  of  sugar  formation  from  the  unit 
of  protein  in  different  animals.  That  these  eventualities  explain  entirely 
variations  in  glucose :  nitrogen  ratios,  is  not,  however,  asserted.  The 
higher  ratios  are  seen  in  the  earlier  days,  and  depend  on  the  conversion 
of  hepatic  glycogen  into  sugar.  Later  the  ratio  is  usually  close  to  3,6  : 1, 
19 


290  METABOLISM 

When  to  such  a  starving  animal,  fully  intoxicated  with  phloridzin, 
sugar  is  administered,  it  will  not  be  burned,  it  will  be  eliminated,  the 
variations  being  slight  and  irregular.  If  lactic  acid  be  administered,  the 
glucosuria  will  be  increased.  Glycerol  has  the  same  action.  And  these 
two  experiments  constitute  beautiful  illustrations  of  the  reversibility  of 
reactions. 

When  fats  are  ingested,  the  glucosuria  is  not  increased.  It  has  been 
stated,  on  experimental  grounds  that  do  not  afford  a  basis  for  positive 
confidence,  that  the  administration  of  fat  in  excess  to  a  phloridzinized 
animal  is  followed  by  the  deposition  of  glycogen  in  the  muscles,  though 
not  in  the  liver.  The  amounts  reported  are  not  enough  to  exclude  the 
glycerol  of  the  fats  as  the  responsible  source. 

When  protein  (protein  free  of  preformed  carbohydrate)  is  adminis- 
tered, the  sugar  in  the  urine  rises  and  maintains  a  relation  in  each 
animal,  quite  parallel  to  the  curve  of  nitrogen  elimination.  Many 
amino-acids  have  the  same  result  upon  the  glucosuria.  Glucose  is 
formed  from  some  of  the  amino-acids  of  the  catabolized  protein,  and 
some  may  be  burned,  though  largely  eliminated.  In  such  phloridzinized 
dogs  many  of  the  most  conclusive  demonstrations  of  the  formation 
of  sugar  from  protein  have  been  accomplished.  Phloridzin  does  not 
in  itself  exaggerate  the  protein  catabolism.  On  account  of  the  losses 
of  glucose  in  the  urine,  the  body  exaggerates  the  catabolism  of  protein 
to  cover  its  needs.  Since  the  burning  of  protein  is  an  expensive  way  of 
supporting  the  body  heat,  and  especially  in  connection  with  the  constant 
loss  of  sugar,  the  heat  metabolism  is  greatly  exaggerated.  Much  fat 
will  be  burned,  if  available,  and  this  leads  to  the  acetone  complex,  to 
acidosis. 

Marked  fatty  infiltration  of  the  liver  occurs  in  connection  with 
phloridzin  intoxication.  This  is  another  illustration  of  the  antagonism 
between  fat  and  glycogen  in  the  liver.  There  being  no  glycogen,  fat 
wanders  in,  the  liver  cells  being  normal.  If  a  heavy  sugar  input  be 
accomplished,  or  if  the  administration  of  phloridzin  be  discontinued, 
the  glycogen  will  return  to  the  liver  and  the  fat  will  emigrate  to  the 
peripheral  fatty  depots. 

Natural  Renal  Glucosuria.  —  Does  renal  glucosuria  occur  as  a  state 
of  disease?  Mention  was  made  of  the  possibility  of  the  glucosuria  of 
salt  injections  and  of  caffein  being  in  part  at  least  the  expressions  of 
a  lowering  of  the  renal  retention  of  glucose.  In  some  diseases  of  the 
kidney,  notably  in  the  arteriosclerotic  type  of  gout  and  in  the  arterio- 
sclerotic form  of  chronic  nephritis,  glucosuria  is  common.  It  is  in  just 
these  cases  that  the  renal  level  for  uric  acid  is  known  to  be  raised.  It 
is  possible  that  here  the  renal  level  for  sugar  may  be  lowered.  Careful 
investigations,  with  controlled  and  varied  relations  of  diet  and  with 
frequent  analyses  of  the  glucose  of  the  blood,  would  probably  afford 
a  definite  decision.  Since  these  individuals  are  helped  rather  than 
harmed  by  venesection,  little  difficulty  need  be  expected  from  this 
direction.    A  complication,  however,  would  lie  in  the  fact  that  follow- 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         291 

ing  venesection,  a  rise  occurs  in  the  sugar  concentration  of  the  blood. 
Nevertheless,  in  view  of  the  great  difficulties  attending  the  production 
of  chronic  nephritis  in  animals,  such  investigations  offer  promise  of 
results. 


THE   CARBOHYDRATE   METABOLISM   IN   DIABETES 

The  disturbances  of  metabolism  in  diabetes  are  of  such  importance 
that  an  understanding  of  them  affords  conceptions  of  metabolism  at 
present  of  greater  value  to  the  physician  than  any  derived  from  the 
study  of  any  other  disease.  Many  of  the  cardinal  facts  of  metabolism 
have  been  determined  through  the  study  of  diabetes  and  allied  condi- 
tions. In  diabetes,  clinical  as  well  as  experimental,  we  are  able  to  view 
and  to  follow  definite  alterations  in  the  chemical  procedures  in  the 
body.  Of  all  diseases,  outside  of  the  microorganismal  infections, 
diabetes  permits  of  experimental  production  in  the  most  classical 
manner;  and  the  inter-interpretation  of  the  facts  of  clinical  and  experi- 
mental diabetes  has  afforded  striking  illumination  of  the  clinical  disease. 
Finally,  we  have  in  diabetes  the  best-known  instance  of  an  auto- 
intoxication. It  will  be  advantageous  to  discuss  seriatim  the  disturb- 
ances in  metabolism  that  are  known  to  occur  in  this  disease. 

Definition  of  Diabetes. — It  will  be  necessary  in  the  first  place  to 
define  the  use  of  the  term  diabetes.  The  facts  determined  for  diabetes 
due  to  removal  of  the  pancreas  in  the  dog,  may  in  many  instances  be 
utilized  as  a  control  in  our  definition  of  the  clinical  term  diabetes. 
From  the  standpoint  of  the  student  of  metabolism,  diabetes  in  the 
human  subject  may  be  more  accurately  defined  than  has  been  possible 
according  to  usual  clinical  standards.  For  the  definition  of  the  momen- 
tary status  of  an  instance  of  glucosuria,  it  is  a  clinical  rule  that  if  the 
condition  subsides  promptly  on  the  withdrawal  of  carbohydrate  from 
the  diet,  true  diabetes  does  not  exist.  Occasionally  a  typical  case  of 
diabetes  develops  in  an  individual  who  for  a  time  previous  has  exhibited 
nothing  but  an  alimentary  glucosuria,  a  lowered  limit  of  assimilation 
for  carbohydrates.  In  the  instances  of  glucosuria  that  persist  after 
the  withdrawal  of  carbohydrate  from  the  diet,  the  younger  the  sub- 
jects the  larger  will  be  the  proportion  of  cases  of  typical  diabetes. 
We  may  group  these  cases  of  extra-alimentary  glucosuria  under  three 
headings. 

(a)  Classical  diabetes,  most  often  seen  in  those  under  middle  life, 
of  acute  or  relatively  rapid  onset;  causeless  so  far  as  the  subject  is  able 
to  determine;  not  preceded  by  disease  of  the  liver,  gout,  obesity  or 
other  known  condition;  of  rapid  course,  and  exhibiting  all  the  metabolic 
abnormalities  to  be  later  detailed;  paralleling  pancreatic  diabetes  in 
the  dog  and  proceeding  relentlessly  to  a  fatal  termination.  Lesions 
of  the  pancreas — rarely  gross,  sometimes  leading  to  a  more  or  less 
complete  distruction  of  the  gland,  involving  specifically  or  solely  the 


292  METABOLISM 

islands  of  Langerhans  and  resulting  in  their  atrophy  and  disappearance 
— are  found  in  practically  all  bodies  dead  of  such  diabetes. 

(b)  Instances  of  diabetes  that  begin  in  simple  alimentary  glucosuria, 
and  pass  slowly  and  insensibly  into  typical  forms  of  diabetes,  differing 
from  those  under  subheading  (a)  only  in  much  greater  chronicity. 
The  majority  of  these  cases  of  diabetes  are  to  be  seen  in  after-middle 
life.  Some  of  these  present  every  metabolic  sign  of  diabetes;  many, 
however,  do  not;  in  particular  the  power  of  forming  and  of  burning  fat 
is  often  retained. 

(c)  Instances  of  diabetes  that  are  apparently  founded  upon  previous 
disease,  as  gout,  arteriosclerosis,  obesity,  or  cirrhosis  of  the  liver. 
While  a  small  percentage  of  the  cases  thus  determined  to  possess  gluco- 
suria on  a  diet  free  of  carbohydrate  do  develop  into  typical  diabetes  with 
all  the  metabolic  signs  of  the  disease,  the  larger  proportion  of  them  do 
not  present  all  the  metabolic  signs,  the  power  of  forming  and  burning 
fat  being  most  often  retained.  One  meets  with  instances  in  which 
through  years  glucosuria  persists  despite  all  regimen,  without  emacia- 
tion, free  of  the  acetone  complex,  with  few  of  the  symptoms  of  diabetes. 
It  is  in  the  bodies  of  those  who  have  suffered  from  diabetes  of  the 
forms  under  (6)  and  (c)  that  lesions  of  the  pancreas  may  be  missed, 
and  specifically  the  islands  of  Langerhans  are  to  be  observed  in  normal 
or  reduced  numbers. 

Etiology  of  Diabetes. — So  far  as  we  have  experimental  knowledge, 
the  pancreas  is  the  only  organ  the  loss  of  whose  function  is  followed 
by  diabetes.  There  is  experimental  evidence  that  the  internal  secre- 
tions of  the  thyroid  and  adrenal  bodies  are  antagonistic  to  that  of  the 
pancreas;  and  that  exaggeration  of  the  function  of  these  bodies  tends 
to  the  depression  of  the  internal  function  of  the  pancreas  and  of  the 
combustion  of  glucose.  But  there  is  no  evidence,  clinical  or  experi- 
mental, that  such  exaggerations  of  the  functions  of  the  thyroid  or 
adrenal  bodies  ever  so  far  depresses  the  internal  function  of  the  pan- 
creas as  to  cause  diabetes,  though  experimentally  they  may  intensify 
glucosuria.  So  long  as  we  possess  no  further  knowledge  it  will  be  safe 
to  refer  to  the  pancreas,  directly  or  indirectly,  the  etiology  of  all  cases 
of  typical  diabetes,  whether  the  histological  examination  with  present 
methods  reveals  alterations  or  not. 

The  clinician,  on  the  other  hand,  must  realize  that  glucosuria  merely, 
even  ex  amylo  or  persisting  after  the  complete  withdrawal  of  all  carbo- 
hydrate from  the  diet,  will  probably  not  be  found  in  the  future  to  be 
an  absolute  criterion  of  diabetes.  The  fundamental  defects  of  the 
diabetic  metabolism  are  inability  to  burn  sugar  and  inability  to  burn 
fat  as  in  the  normal.  There  is  evidence  that  hyperglucemia  and  gluco- 
suria may  persist  in  a  body  that  burns  fat  perfectly  and  sugar  fairly 
well;  in  whom,  in  short,  there  is  but  a  partial  defect.  This  partial  defect 
may  indeed  become  complete.  But  it  may  remain  stationary  and  the 
subject  live  indefinitely  in  that  condition.  The  normal  man  has  an 
almost  unlimited  power  of  burning  sugar.    This  may  be  greatly  reduced 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES        293 

without  the  man  becoming  a  typical  diabetic,  and  without  the  other 
metabolic  disturbances  of  classical  diabetes  becoming  established. 

It  has  been  long  assumed,  in  a  half-conscious  manner  that  has  rarely 
found  definite  expression  inside  of  the  physiological  laboratory  but 
which  has  nevertheless  moulded  past  conceptions  of  the  disease,  that 
there  is  a  total  suboxidation  in  diabetes.  By  this  we  mean  that  the 
total  combustions  in  the  diabetic  body  are  less  than  in  the  normal. 
By  fuller  utilization  of  the  mechanism  of  heat  dissipation  (such  as 
occurs  in  myxodema)  it  would  be  possible  to  maintain  the  body  tempera- 
ture on  a  plane  of  total  oxidation  considerably  lower  than  the  normal, 
though  with  a  corresponding  restriction  of  the  function  of  adaptation 
of  the  organism.  But  the  direct  experiment,  the  measurement  of 
heat  production  in  the  diabetic  by  the  methods  of  direct  and  indirect 
calorimetry,  has  demonstrated  the  incorrectness  of  this  assumption. 
In  fact,  the  total  heat  production  of  the  diabetic  body  is  found  to  be 
a  little  above  the  normal,  6  to  7  per  cent.  A  calculation  of  the  data 
obtained  from  dogs  with  experimental  diabetes  leads  to  the  same  con- 
clusion. This  is  exactly  what  should  have  been  expected  on  mechanical 
as  well  as  thermodynamic  grounds.  It  takes  more  fuel  to  get  ten 
horse-power  out  of  a  worn  ten  horse-power  engine  than  out  of  one  in 
perfect  condition;  and  it  requires  more  fuel  to  yield  2000  Calories  of 
heat  available  in  terms  of  cellular  energy  in  the  disturbed  metabolism 
of  the  diabetic  body  than  in  the  normal  individual.  While  it  is  true 
that  the  diabetic  has  lost  in  whole  or  in  part  the  power  of  burning 
glucose,  the  power  of  burning  most  other  substances  is  retained.  Since 
the  total  combustions  are  normal  or  excessive  and  the  combustion  of 
glucose  low,  it  must  follow  that  the  combustion  of  fat  and  protein 
though  qualitatively  abnormal  is  still  excessive;  and  this  is  the  fact, 
determined  by  direct  test.  In  the  terminal  stages  of  diabetes,  as  in 
diabetic  coma,  the  total  combustions  of  the  body  are  probably  reduced 
below  the  normal. 

A  mechanical  illustration  will  make  the  matter  clear.  Modern 
marine  boilers  are  installed  for  heating  by  the  burning  of  crude  oil 
or  of  coal,  the  fire-box  having  a  double  installation.  Now  the  installa- 
tion for  burning  oil  may  become  disabled  without  the  installation 
for  the  burning  of  coal  being  in  the  least  disturbed;  under  such  circum- 
stances steam  would  be  kept  up  by  the  burning  of  coal.  So  in  the 
diabetic  body,  the  installation  for  the  burning  of  glucose  breaks  down, 
that  for  the  burning  of  protein  and  fat  is  retained,  and  the  body  pro- 
duces heat  by  the  combustion  of  these  substances.  As  will  be  later 
pointed  out,  frequently  the  installation  for  the  combustion  of  fat 
breaks  down  also,  leaving  the  poor  diabetic  body  with  very  defective 
means  to  maintain  heat  production.  Even  under  these  extreme  cir- 
cumstances, the  power  of  the  body  to  burn  many  extraneous  chemical 
substances  is  not  reduced,  and  the  total  heat  production  is  at  least 
normal. 

It  is  important  in  this  connection  to  make  one  further  point  clear. 


294  METABOLISM 

While  the  total  combustions  of  the  resting  body  in  diabetes  are  normal 
or  excessive,  the  facultative  increase  of  combustion  in  the  sense  of 
the  normal  power  of  work  is  always  lowered.  To  the  point  of  absolute 
muscular  exhaustion,  the  normal  individual  can  increase  the  combus- 
tions of  the  body  for  the  support  of  work;  the  limit  of  muscular  work 
lies  in  the  fatigue  of  heart  and  neuromuscular  apparatus,  not  in  any 
limit  of  combustion.  With  the  diabetic,  however,  this  facultative 
increase  of  combustion  for  the  support  of  muscular  work  is  limited; 
in  marked  degree,  it  is  true,  only  in  severe  diabetes. 

Experimental  Diabetes. — It  will  be  of  advantage  at  the  outset  to 
sketch  the  known  facts  of  experimental  diabetes.  This  is  provoked 
by  the  abolition  of  the  internal  function  of  the  pancreas,  either  by 
extirpation  or  atrophy  of  the  organ.  Complete  extirpation  of  the 
pancreas  in  the  dog  is  followed  within  a  few  hours  by  glucosuria,  the 
to-be-enumerated  metabolic  defects  develop  rapidly,  the  animal  wastes, 
the  wound  of  operation  usually  refuses  to  heal  and  the  animal  dies 
within  a  few  weeks  of  septic  infection  or  diabetes.  The  behavior  of 
the  wound  of  operation  in  the  dog  is  in  striking  similarity  to  the  be- 
havior of  human  diabetic  tissues  under  operations,  long  known  through 
unfortunate  experience  to  exist  in  the  human  subject  with  diabetes, 
in  whom  sepsis  and  gangrene  occur  upon  slight  provocation.  In  older 
dogs,  the  reaction  of  the  animal  is  more  favorable,  the  wound  heals, 
the  duration  of  life  is  prolonged,  and  polyuria,  polydipsia,  and  poly- 
phagia develop  in  characteristic  manner.  In  the  rapid  decline  to  be 
often  observed,  especially  in  younger  dogs,  in  whom  sepsis  is  the  chief 
cause  of  death  (though  the  intensity  of  this  sepsis  rests  upon  the  reduced 
tissue  resistance  of  diabetes),  the  symptoms  of  polyuria,  polydipsia, 
and  polyphagia  may  not  occur  at  all.  If  a  small  part  of  the  pancreas 
be  left,  with  proper  arterial  and  venous  attachments,  diabetes  will 
not  develop  at  the  time.  If  later  this  piece  be  extirpated  at  a  second 
operation,  diabetes  will  develop  at  once.  In  some  instances,  diabetes 
develops  gradually,  due  to  the  atrophy  of  the  piece  of  pancreas  left 
within  the  body;  in  other  instances,  for  a  year  at  least,  diabetes  has 
not  developed.  If  the  common  pancreatic  duct,  or  ducts,  be  ligated, 
the  gland  will  undergo  a  gradual  atrophy,  and  later  diabetes  will  super- 
vene. In  some  instances,  however,  in  which  the  operation  of  ligation 
has  been  done  with  great  care,  diabetes  has  not  developed  within  a 
year,  the  only  symptom  related  to  the  metabolism  being  a  greatly 
reduced  limit  of  assimilation  of  sugar.  On  section  of  such  an  animal, 
a  mass  of  scar  tissue  is  found  to  occupy  the  site  of  the  pancreas;  and 
in  this  scar  tissue  is  no  trace  of  acinal  pancreatic  tissue,  but  islands  of 
Langerhans  are  to  be  seen.  It  may  be  confidently  believed  that  after 
the  lapse  of  still  longer  time,  when  the  tissue  has  had  opportunity  to 
undergo  complete  atrophy,  which  may  be  greatly  prolonged,  diabetes 
would  develop.  Should  the  experiment  not  justify  this  prediction, 
the  best  explanation  would  be  to  assume  that  the  islands  of  Langerhans 
are  not  derived  from  the  acini  of  the  pancreas,  and  that  complete 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         295 

atrophy  of  the  secretory  portions  of  the  gland  may  occur  with  reten- 
tion of  the  internal  function  of  the  pancreas,  due  to  retention  of  the 
islands  of  Langerhans  in  state  and  number  sufficient  to  maintain 
functions.  It  may  also  be  confidently  predicted  that  if  the  atrophied 
scar  tissue  of  the  site  of  the  pancreas  be  removed,  diabetes  would  develop. 

The  best  method  of  establishing  the  disease  experimentally  is  to  do 
the  operation  in  two  stages,  allowing  a  portion  of  the  gland  to  remain, 
either  to  undergo  atrophy  or  to  be  removed  by  a  later  operation.  The 
operation  succeeds,  i.  e.,  produces  glucosuria  and  inferentially  all  the 
rest,  in  birds,  frogs,  and  lizards. 

Hyperglucemia  is  promptly  produced,  and  is  the  cause  of  the  gluco- 
suria. The  limit  of  assimilation  of  carbohydrates  is  reduced  to  the 
lowest  level.  If  the  liver  be  removed  with  the  pancreas,  which  is 
possible  in  the  frog,  hyperglucemia  and  glucosuria  do  not  occur.  Starva- 
tion lowers  but  does  not  remove  the  glucosuria.  The  explanation  of 
this  fact  is  as  follows:  The  glucose  eliminated  by  the  diabetic  comes 
from  carbohydrates  of  the  diet  and  from  protein,  either  of  the  diet 
or  from  the  tissues  of  the  animal.  The  sugar  derived  from  protein 
is  formed  in  the  liver.  With  the  liver  removed,  therefore,  there  is  no 
formation  of  glucose  from  protein  and  consequently  no  glucosuria. 

At  autopsy,  the  liver  and  muscles  are  found  to  be  very  poor  in, 
or  totally  free  of,  glycogen.  The  liver,  muscles  and  blood  are,  however, 
rich  in  fat.  These  results  remind  one  of  the  findings  in  starvation. 
The  blood  will  not  produce  glucosuria,  or  any  other  result,  on  injec- 
tion in  large  amounts  into  a  healthy  animal.  Nor  will  the  injection 
of  the  blood  of  a  healthy  dog  have  the  slightest  effect  on  the  glucosuria 
of  the  depancreatized  animal.  The  blood  of  the  diabetic  dog  does  not 
display  any  alteration  in  the  normal  slight  glycolytic  activity.  The 
administration  by  mouth  or  hypodermic  injection,  of  pancreatic  extracts 
has  no  influence  upon  the  course  of  the  metabolism. 

If  the  dog  be  reduced  to  the  lowest  level  of  starvation  before  the 
operation,  glucosuria  may  not  occur,  only  a  moderate  hyperglucemia. 
Though  little  sugar  can  be  burned  by  such  an  animal,  still  less  is  formed 
in  the  atrophied  state  of  the  tissues.  This  fact  does  not  speak  for  or 
against  the  possible  origin  of  sugar  from  fat.  The  administration  of 
epinephrin  exaggerates  the  glucosuria  in  early  cases.  This  is  due  to  the 
fact  that  this  substance  stimulates  the  glycolytic  function  of  the  liver 
to  even  more  than  the  already  abnormal  extent  present  in  diabetes. 
When  the  liver  has  been  cleared  out,  so  to  speak,  further  injections  of 
epinephrin  have  no  further  action  in  this  direction. 

It  has  been  stated  that  ablation  of  the  pancreas  in  the  pregnant  dog 
does  not  result  in  diabetes,  the  interpretation  being  obviously  that  the 
internal  secretions  of  the  pancreas  of  the  young  in  the  uterus  pass  into 
the  maternal  circulation  and  carry  on  the  function.  In  the  human 
subject,  pregnancy  does  not  act  as  a  positive  influence  upon  diabetes. 

All  the  metabolic  defects  in  the  diabetic,  to  be  detailed  seriatim, 
hold  in  the  diabetes  of  the  depancreatized  dog.     It  is  not  common, 


296  METABOLISM 

except  in  the  late  stages,  for  the  function  of  combustion  of  sugar  to 
be  entirely  lost,  though  it  is  always  very  low.  The  glucose:  nitrogen 
ratio  runs  about  2.7  to  3  :  1,  it  may  be  as  low  as  2  :  1,  or  as  high  as 
5:1.  When  it  is  recalled  that  it  was  with  the  dog  that  the  so-called 
normal  ratio,  supposed  to  represent  the  relation  of  the  formation  of 
sugar  from  protein  (4.4  :  1)  was  established,  one  is  led  to  infer  that 
the  diabetic  dogs  still  burn  some  glucose. 

The  sum  total  of  our  experience  with  pancreatic  diabetes  runs  to 
the  effect  that  the  pancreas  forms  an  internal  secretion  that  in  some 
way  is  essential  in  the  muscles  to  the  combustion  of  sugar,  carrying 
what  in  a  general  way  may  be  termed  the  function  of  a  co-ferment 
or  zymo-excitor.  The  pancreas  does  not  itself  form  a  glucolytic  fer- 
ment, but  it  does  form  something  that  is  in  some  way  necessary  for 
the  combustion  of  glucose  by  the  muscle  cells.  Whether  all  the  other 
defects  in  the  metabolism  of  the  diabetic  are  secondary  to  this  or 
whether  the  removal  of  the  pancreas  affects  directly  other  acts  of  metab- 
olism, notably  the  formation  and  combustion  of  fat,  will  be  discussed 
later.  When  an  extract  of  pancreas  is  mixed  with  an  extract  of  muscle 
and  a  solution  of  glucose,  the  glucose  disappears  in  part.  Properly 
executed,  there  is  no  question  of  the  fact  of  this  result.  Recent  experi- 
ments, however,  indicate  that  the  glucose,  instead  of  being  burned 
(lactic  acid  or  alcohol  have  never  been  demonstrated  in  the  mixture), 
has  been  converted  into  a  maltose.  In  other  words,  the  experiment 
yields  the  condensation  or  polymerization  function  of  the  muscle, 
(of  which  the  physiological  expressions  are  the  formation  of  maltose 
and  glycogen  from  glucose  in  the  muscle  cell)  instead  of  the  combustion 
of  sugar.  It  is  not  now  possible  to  make  any  definite  statement  of  the 
relation  of  the  pancreas  to  the  muscle.  Certain  only  is  the  fact  that 
in  some  chemical  way  the  pancreas  cooperates  with  the  muscle  in 
the  combustion  of  sugar.  It  is  the  conviction  of  most  workers  that 
this  internal  function  of  the  pancreas  is  localized  in  the  islands  of 
Langerhans. 

Physiologists  who  endeavor  to  locate  the  etiology  of  diabetes  in  the 
central  nervous  system,  have  for  two  reasons  objected  to  the  inter- 
pretation of  the  results  of  extirpation  of  the  pancreas  here  given;  firstly, 
that  extirpation  of  the  duodenum  produces  glucosuria;  and  secondly, 
that  the  results  of  extirpation  of  the  pancreas  persist  when  pancreatic 
extracts  are  injected  into  the  animals.  That  extirpation  of  the  duo- 
denum causes  a  glucosuria  is  true;  but  that  extirpation  of  the  duodenum, 
without  injury  to  the  pancreas,  causes  a  diabetes  with  the  metabolic 
disturbances  known  to  exist  in  pancreatic  diabetes,  has  not  been  shown 
at  all.  The  second  objection  carries  more  weight,  though  it  is  not 
now  tenable.  The  results  of  extirpation  of  the  thyroid  body  are  com- 
pletely nullified  by  injection  with  thyroid  extracts,  and  it  is  assumed 
that  the  same  ought  to  hold  for  the  pancreas.  But  for  this  line  of 
argument  to  hold,  it  would  need  to  be  assumed  that  the  metabolic 
products  of  all  tissues  are  stable,  as  thyroid  substance  is  —  a  conten- 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES        297 

tion  that  no  physiological  chemist  could  concede.  Not  only  may  the 
substance  supposedly  formed  in  the  pancreas  be  unstable,  it  is  also 
probable  that  it  is  continuously  secreted,  and  that  the  gland  contains 
at  the  one  moment  of  preparation  of  the  extract  only  the  merest  trace 
of  the  substance.  The  experiment  contains  so  many  possibilities  of 
error  that  the  present  failure,  or  even  the  definite  failure,  of  injections 
of  pancreatic  extracts  is  not  a  valid  objection  to  the  interpretation 
of  the  facts  given — that  the  pancreas  furnishes  to  the  body  a  chemical 
substance  essential  in  the  muscles  to  the  normal  combustion  of  sugar. 

The  fact  that  acromegaly  is  sometimes  associated  with  diabetes  is  not 
out  of  harmony  with  the  statement  that  the  pancreas  is  the  only  tissue 
of  the  body  whose  removal  will  provoke  diabetes.  The  relations  of 
acromegaly  to  diabetes  are  certainly  unclear.  But  lesions  of  the  hypo- 
physis or  the  removal  of  that  body  does  not  lead  to  the  establishment 
of  diabetes,  as  in  the  case  of  removal  of  the  pancreas ,  though  the  limit 
of  assimilation  of  carbohydrates  is  disturbed.  The  experimental  data 
are  not  clear-cut  at  present,  and  in  part  even  contradictory.  But  in  a 
tentative  way  we  may  define  the  relations  of  the  hypophysis  to  the 
metabolism  of  carbohydrate  as  follows:  Overfunctionation  of  the  body 
results  in  lowering  of  the  toleration  for  carbohydrates;  upon  what  this 
is  founded,  is  not  known.  Deficient  functionation,  as  ablation,  increases 
the  toleration  of  the  body  for  carbohydrates,  the  animals  will  tolerate 
without  glucosuria  large  injections  of  glucose.  The  mechanism  of  this 
increased  toleration  is  not  clear;  in  particular,  we  do  not  know  whether 
it  is  due  to  hyperglucemia  with  increased  impermeability  of  the  kidneys 
or  to  increased  glycogenesis.  The  dogs  who  have  undergone  this  oper- 
ation tend  to  fatten  rapidly,  which  is  what  would  be  expected  in  accord- 
ance with  the  law  of  mass  action.  The  relations  of  these  functions  to 
the  pancreas  are  unclear. 

In  all  discussions  of  the  relations  of  disease  of  the  pancreas  to  diabetes, 
it  must  be  understood  that  disease  of  the  pancreas  in  toto  is  not  present. 
It  is  rare  even  in  the  typical  rapid  diabetes  of  youth,  for  the  intestinal 
functions  of  the  pancreas  to  be  in  the  least  disturbed.  On  the  other 
hand,  obstruction  of  the  common  pancreatic  duct  or  tumors  of  the 
pancreas  do  not  lead  to  diabetes  unless  atrophy  of  the  whole  tissue 
follows.  The  secretory  function  of  the  pancreas  as  a  digestive  gland 
and  the  internal  function  of  the  pancreas  as  related  to  the  metabolism 
of  carbohydrate,  are  separate  and  independent  functions.  We  have 
only  to  review  the  work  of  the  liver  to  realize  how  many  chemical 
functions  may  devolve  upon  one  organ.  This  conception  is  made 
more  easy  in  the  case  of  the  pancreas  by  the  fact  that  whatever  their 
origin,  in  their  adult  state  the  acini  and  the  islands  of  Langerhans 
are  different  structures. 

The  Combustion  of  Glucose. — Reduction  in  the  power  of  burning 
glucose  is  the  fundamental  defect  of  the  disturbed  metabolism  of 
diabetes.  No  mystical  appeal  to  the  central  nervous  system  as  the 
seat  of  diabetes  can  alter  this  established  fact.    We  have  here  another 


298  METABOLISM 

illustration  of  an  old  theory  coming  into  its  own.  Just  as  we  today 
accept  the  theory  of  fermentation  enunciated  a  half  century  ago  by 
a  long-visioned  chemist,  so  we  have  through  the  experimental  investi- 
gations into  diabetes  established  the  truth  of  the  teaching  of  the  physio- 
logically trained  clinicians  of  nearly  a  half  century  ago,  that  the  defect 
in  diabetes  lies  in  the  inability  to  split  the  molecule  of  glucose  prelimi- 
nary to  oxidation.  It  is  now  an  established  fact  that  fat,  protein, 
and  sugar  must  all  be  split  before  they  are  available  for  oxidation  in 
the  body.  The  investigations  into  the  fermentation  of  sugar  indicate 
that,  disregarding  earlier  intermediary  stages,  the  molecule  of  glucose 
must  be  split  into  two  molecules  of  lactic  acid  before  it  can  be  converted 
into  alcohol.  In  the  animal  body,  according  to  our  present  evidence, 
the  molecule  of  glucose  must  be  split  into  two  molecules  of  lactic  acid 
before  it  can  be  burned.  The  cleavage  into  lactic  acid  is  probably  not 
direct,  as  indicated  in  another  connection.  Intermediary  stages,  as 
yet  not  clearly  defined  in  the  chemical  sense,  undoubtedly  appear 
earlier  than  lactic  acid.  Methylglyoxal,  in  one  form  or  other,  seems 
a  likely  intermediary  stage.  But  for  the  present  we  may,  in  the  practical 
application  of  this  teaching  to  diabetes,  rest  with  the  statement  that 
the  diabetic  cannot  split  glucose  into  lactic  acid.  From  the  stage  of 
lactic  acid  on,  through  ethyl  alcohol,  assuming  that  such  is  the  direc- 
tion of  the  oxidation  in  the  animal  body,  the  powers  of  the  diabetic 
organism  are  normal;  but  the  formation  of  lactic  acid  from  glucose 
the  diabetic  body  cannot  accomplish.  The  formation  of  glucose  from 
lactic  acid  the  diabetic  body  can  accomplish  as  in  the  normal;  but  the 
cleavage  of  glucose  into  lactic  acid,  the  diabetic  cannot  accomplish. . 

Relations  between  Glucose  and  Lactic  Acid. — It  is  necessary  at  this 
point  to  expound  a  little  more  in  detail  the  reciprocal  relations  of 
glucose  and  lactic  acid.  The  facts  are  capable  of  a  simple  interpreta- 
tion according  to  the  law  of  mass  action.  Whenever  the  concentration 
of  lactic  acid  is  low,  the  reaction  runs  in  the  direction  of  the  formation 
of  lactic  acid ;  when  the  concentration  of  lactic  acid  is  high,  the  reaction 
runs  in  the  direction  of  the  formation  of  glucose.  In  the  muscles, 
where  the  combustion  of  sugar  occurs,  the  intermediary  lactic  acid 
appears  but  in  traces,  and  is  there  quickly  oxidized.  When,  however, 
a  large  amount  of  lactic  acid  is  ingested  and  absorbed,  the  concentra- 
tion of  lactic  acid  in  the  liver  and  probably  also  in  the  blood,  is  so 
great  that  the  direction  of  the  reaction  is  reversed,  and  glucose  is 
formed.  Small  amounts  of  lactic  acid  are  burned  in  the  normal  body, 
in  the  dog  with  phloridzin  intoxication  and  in  the  diabetic;  larger 
amounts  result  in  the  formation  of  glucose  under  all  three  conditions. 
It  is  clear,  therefore,  especially  in  consideration  of  the  existence  of 
hyperglucemia,  that  the  diabetic  would  be  able  to  complete  the  oxida- 
tion of  glucose  in  the  normal  manner  if  once  glucose  could  be  converted 
into  lactic  acid. 

Contrary  to  earlier  opinions,  the  combustion  of  glucose  occurs  largely 
in  the  muscles,  not  in  the  liver.    The  muscles  we  may  regard  as  the 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         299 

fire-box  of  the  body.  The  pancreas  contributes  some  chemical  factor 
to  this  muscular  metabolism,  and  when  this  contribution  of  the  pan- 
creas is  lacking,  the  power  of  the  muscle  to  split  glucose  into  lactic 
acid  is  impaired  or  lost.  This  in  a  nutshell  is  the  present  conception 
of  the  non-combustion  of  sugar  in  diabetes. 

Demonstration  of  Non-combustion  of  Glucose. — The  fact  of  the  non- 
combustion  of  glucose,  or  at  least  its  greatly  reduced  combustion,  in 
diabetes  can  be  demonstrated  in  several  ways.  In  one  of  the  crucial 
animal  experiments  in  diabetes,  a  dog  weighing  5.8  kilos,  whose  body 
under  the  conditions  of  the  experiment  could  not  have  contained  over 
250  grams  of  stored  glycogen  and  sugar,  was  made  diabetic  by  ablation 
of  the  pancreas.  He  was  fed  on  nutrose  (a  casein  compound  free  of 
preformed  carbohydrate)  and  during  twenty-five  days  eliminated 
nearly  1200  grams  of  sugar.  A  kilo  of  sugar  was  eliminated  from  a 
non-carbohydrate  source  by  an  animal  of  but  little  over  five  times 
that  weight,  in  less  than  a  month.  This  experiment,  which  first  demon- 
strated indisputably  the  formation  of  sugar  from  protein  or  fat,  demon- 
strates at  the  same  time  the  lack  of  combustion  of  sugar  in  the  animal, 
since  obviously  such  an  amount  of  sugar  could  not  have  been  eliminated 
under  these  circumstances  if  the  body  were  utilizing  it  in  its  heat 
metabolism.  The  only  intelligible  interpretation  of  the  result  is  that 
the  body  was  forming  sugar  (from  protein  certainly  and  possibly  from 
fat),  and  eliminating  it  because  it  could  not  be  burned.  This  same 
fact  is  seen  in  clinical  diabetes.  The  blood  and  tissues  are  flooded 
with  glucose  (hyperglucemia) ;  if  the  carbohydrate  of  the  diet  be  in- 
creased, the  increase  appears  almost  quantitatively  in  the  urine;  if 
carbohydrate  be  stricken  from  the  diet  the  glucosuria  falls;  if  the 
meat  of  the  diet  be  raised,  the  glucosuria  will  rise;  if  the  meat  be  reduced, 
the  glucosuria  falls.  However  derived — from  carbohydrate  of  the  diet, 
from  meat  of  the  diet  or  from  the  body  flesh — the  sugar  is  largely 
eliminated  and  only  burned  to  a  limited  extent. 

The  respiratory  quotient  indicates  the  same  fact  of  the  non-combus- 
tion of  glucose.  The  respiratory  quotient  on  the  maintenance  of  the 
body  heat  by  the  combustion  of  glucose  is  nearly  1 ;  by  the  combustion 
of  fat  it  is  something  over  0.7;  by  the  combustion  of  protein  it  is  about 
0.8.  Now  in  diabetes  the  respiratory  quotient,  coexisting  with  hyper- 
glucemia and  glucosuria,  varies  from  0.6  to  0.8  (below  0.7,  for  reasons 
that  will  be  detailed  later);  in  other  words,  the  diabetic  presents  the 
respiratory  quotient  of  an  organism  supporting  its  heat  mechanism 
largely  or  wholly  by  the  combustion  of  fat  and  protein.  If  a  dog  be 
freed  of  glycogen  by  work,  starvation  or  refrigeration,  and  then  placed 
at  work,  it  will  be  found  to  have  a  respiratory  quotient  of  from  0.7  to 
0.8,  since  it  is  supporting  its  heat  mechanism  on  the  combustion  of 
fat  and  protein.  If  to  such  a  dog  carbohydrate  be  given,  the  respira- 
tory quotient  will  rise  in  a  short  time.  When,  however,  carbohydrate 
is  given  to  a  diabetic  the  respiratory  quotient  will  not  rise,  but  instead 
the  carbohydrate  will  be  eliminated  in  the  urine  in  the  form  of  sugar. 


300  METABOLISM 

The  failure  of  the  combustion  of  sugar  can  also  be  shown  by  another 
calculation.  The  heat  production  being  known,  the  nitrogen  input 
and  output,  and  the  sugar  input  and  output,  it  can  be  made  certain 
(barring  the  formation  of  sugar  from  fat)  that  the  body  heat  is  supported 
by  the  combustion  of  protein  and  fat,  and  that  the  sugar  formed  from 
protein  or  ingested  in  the  state  of  carbohydrate  is  eliminated  in  the 
urine.  Such  calculation,  made  roughly  in  clinical  diabetes,  gives  a 
very  fair  indication  of  the  degree  of  utilization  of  carbohydrate  in  the 
heat  metabolism.  Such  a  calculation  has  the  advantage  over  the  use 
of  the  glucose :  nitrogen  ratio,  to  be  mentioned  later,  in  that  the  fluctua- 
tions in  the  nitrogen  factor  are  controlled.  The  heat  production  can- 
not, of  course,  be  usually  measured;  but  it  may  be  approximated  by 
calculation  of  30  to  35  Calories  per  kilo  body  weight  per  day.  The 
mere  measurement  of  the  carbohydrate  input  and  sugar  output  may 
lead  to  valuable  results  in  mild  cases;  but  in  severe  cases,  where  the 
sugar  output  exceeds  the  carbohydrate  input,  the  nitrogen  input  and 
output  must  also  be  measured. 

The  fact  that  the  combustions  of  the  body  in  diabetes  are  largely 
confined  to  protein  and  fat,  is  clearly  shown  in  the  caloric  equivalents 
that  have  been  determined  in  the  disease.  The  following  table  contains 
the  equivalents  for  the  different  foodstuffs,  and  in  the  lower  space  those 
that  have  been  observed  in  diabetes: 

Caloric  equivalent  of  1  gram. 
CO2  Oxygen. 

Glucose 2.56  3.52 

Protein 2.90  3.22 

Fat 3.42  3.30 

Observed  in  diabetes 3.26  3.30 

It  is  clear  that  the  observed  equivalents  in  diabetes  have  been  attained 
largely  through  the  combustion  of  fat  and  protein,  since  they  are  far 
removed  from  the  figures  for  glucose.  The  C02  elimination  in  diabetes 
indicates  directly  the  lack  of  combustion  (or  toleration)  of  glucose. 
In  severe  diabetes,  the  C02  elimination  is  quite  constant  from  day  to 
day,  irrespective  of  the  variations  in  the  carbohydrate  of  the  diet. 
Variation  in  the  input  of  carbohydrate  is  followed  by  fluctuation  in  the 
output  of  C02  in  a  body  being  heated  by  the  combustion  of  sugar. 

From  the  dynamic  point  of  view  the  failure  to  burn  sugar  in  the 
diabetic  is  all  the  more  striking  when  viewed  in  connection  with  the 
excess  of  sugar  in  the  blood.  This  should,  unless  otherwise  removed, 
lead  to  increase  in  the  rate  of  combustion.    But  the  ferment  is  inactive. 

Amount  of  Combustion  in  Diabetes. — It  is  not  usual,  so  far  as  can  be 
learned,  for  the  power  of  burning  glucose  to  be  entirely  lost,  even  in 
severe  diabetes.  The  difficulties  in  the  way  of  the  accurate  determina- 
tion of  this  point  are  at  present  not  surmountable.  In  the  last  stages 
of  clinical  diabetes,  it  seems  likely  that  no  sugar  is  burned,  just  as  in 
the  last  stages  of  pancreatic  diabetes  in  the  dog.     It  may  probably 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         301 

be  stated  with  approximate  correctness,  that  the  average  diabetic  can 
burn  25  to  50  grams  of  glucose  per  day.  The  normal  individual,  with 
work  or  refrigeration,  can  burn  a  kilo  or  more  of  glucose  per  day. 
According  to  degree  of  severity,  diabetics  may  be  graded.  There 
are  mild  cases  of  true  diabetes  who  can  burn  100  to  150  grams  of  sugar 
per  day  plus  the  amount  derived  from  the  protein  of  the  diet,  say  50 
grams.  As  the  severity  of  the  disease  rises,  these  figures  fall,  until 
we  come  to  a  large  group  of  cases  who  are  able  to  burn  only  the  glucose 
formed  from  the  protein  of  the  diet — 50  to  75  grams  per  day — added 
sugar  in  the  diet  being  eliminated.  The  ingestion  of  an  excess  of  protein 
will  usually  be  followed  by  the  reappearance  of  glucosuria  in  these 
cases.  In  still  more  severe  instances  the  sugar  formed  from  the  protein 
of  the  diet  cannot  be  burned,  and  glucosuria  appears  on  a  protein-fat 
ration.  If  the  protein  be  cut  to  a  low  figure  and  the  fat  be  held  high, 
many  of  these  cases  will  lose  their  glucosuria.  In  others,  however, 
it  will  persist  under  all  circumstances.  And  since,  with  increasing 
severity  of  the  disease,  the  combustion  of  fat  becomes  imperfect  and 
greater  resource  must  be  had  to  the  protein  metabolism,  such  cases 
will  present  heavy  glucosuria  on  the  best  protein-fat  regimen  that  can 
be  maintained.  It  is  not  usual  to  recover  in  the  urine  all  the  sugar 
that  the  protein  can  be  calculated  to  yield.  There  are,  however,  unusual 
cases  in  which  not  only  is  all  the  sugar  to  be  recovered  from  the  urine 
that  can  be  derived  from  the  catabolism  of  the  protein,  but  apparently 
more;  and  in  some  extreme  cases  so  much  more  that  we  are  almost 
compelled  to  assume  a  final  derivation  of  this  sugar  from  the  fats, 
even  under  the  assumption  that  absolutely  no  sugar  is  being  burned. 

If  to  a  diabetic  dog  on  a  fixed  protein-fat  regimen  a  unit  of  sugar 
be  given,  this  will  reappear  quantitatively  in  the  urine.  In  experiences 
with  established  diabetes  in  the  human  subject,  this,  too,  is  the  rule. 
There  are,  however,  cases  in  which,  after  a  time,  less  than  the  added 
unit  of  sugar  appears  in  the  urine;  the  combustion  of  sugar  improves 
and  we  speak  of  the  function  being  improved  by  use.  In  other  cases, 
however,  the  contrary  result  is  attained;  more  than  the  unit  of  sugar 
administered  is  recovered  in  the  urine,  the  patient  has  lost  even  of  his 
already  reduced  powers  of  burning  sugar,  and  we  regard  this  as  an 
expression  of  the  injury  that  the  increased  concentration  of  glucose 
has  done  to  the  metabolism.  Valuable  as  it  is  to  the  diabetic  to  use 
his  powers  of  burning  sugar  to  the  fullest,  even  so  injurious  is  it  to 
him  to  have  his  system  flooded  with  an  excess  of  ingested  glucose  that 
he  cannot  burn. 

The  whole  question,  of  utmost  importance  in  the  treatment  of 
diabetes,  cannot  be  correctly  settled  until  the  purely  physiological 
question  of  the  amount  of  glucose  that  a  body  forms  from  a  unit  of  a 
fixed  protein  is  known.  This  will  be  discussed  under  another  heading. 
For  the  present,  however,  there  is  no  warrant  for  the  idea  that  the 
body  in  diabetes  can  burn  no  sugar.  It  is  certain  that  the  amount 
that  can  be  burned  in  typical  cases  is  very  small.    The  state  of  the 


302  METABOLISM 

glycogen  depots  of  the  body  postmortem  cannot  be  used  as  a  basis 
for  a  judgment  of  the  sugar-burning  powers  of  the  body  before  death. 
These  are  in  all  cases  highly  depleted  and  may  be  exhausted.  But  this 
could  be  the  result  of  defective  glycogenesis  as  well  as  of  excessive 
glycolysis.  So  far  as  the  direct  relations  are  concerned,  there  is  no 
theoretical  reason  why  the  combustion  of  sugar  should  not  cease  with- 
out disturbing  the  depots  of  glycogen.  But  diabetes  represents  no 
such  single  defect  in  the  carbohydrate  metabolism. 

Work  and  the  Combustion  of  Glucose. — Work  increases  to  some  extent 
the  combustion  of  glucose  in  the  body  of  the  diabetic,  in  inverse  propor- 
tion usually  to  the  severity  of  the  disease.  There  can  be  no  question 
that  in  the  cases  where  graduated  exercises  are  associated  with  pro- 
gressive reduction  in  the  elimination  of  sugar  on  a  fixed  diet,  the  power 
of  burning  sugar  is  thereby  progressively  improved.  In  severe  cases 
no  amount  of  exercise  will  be  followed  by  a  reduction  in  the  elimina- 
tion of  sugar.  On  the  contrary,  one  of  two  untoward  effects  may  occur. 
The  sugar  in  the  urine  may  be  increased;  this  will  indicate  that  the 
work  is  being  done  on  the  combustion  of  protein  (of  the  diet  or  of 
tissue),  and  the  increment  of  sugar  in  the  urine  is  derived  therefrom. 
Or  the  acetone  bodies  may  be  increased;  this  indicates  that  the  work 
is  being  done  on  the  combustion  of  fat  and  the  acetone  bodies  serve 
to  illustrate  the  added  defect  in  this  metabolism.  If  the  acidosis  be 
increased,  the  C02  elimination  will  be  augmented  through  expulsion 
of  carbonic  acid  from  the  blood,  due  to  the  reduced  capacity  of  the 
blood  for  carbonic  acid.  This  is  an  illustration  of  the  caution  that 
must  be  employed  in  the  interpretation  of  the  respiratory  quotient, 
since  this  increase  in  CO2  might  have  been  erroneously  regarded  as  due 
to  an  increased  combustion  of  sugar.  In  depancreatized  dogs,  the 
power  of  burning  sugar  for  the  support  of  work  is  directly  proportional 
to  the  power  of  burning  sugar  at  rest.  That  work  in  the  dog  is  done 
on  protein  and  fat  has  been  directly  shown  by  the  determination  of 
the  respiratory  quotient.  But  in  human  diabetes  there  are  striking 
exceptions.  One  meets  with  cases  of  severe  diabetes  with  heavy  gluco- 
suria  and  pronounced  acidosis,  in  whom  obviously  there  is  little  power 
of  burning  sugar  at  rest,  who  nevertheless  under  proper  exercises 
display  striking  reductions  in  both  glucosuria  and  acidosis.  On  the 
other  hand,  in  mild  cases  work  may  be  badly  tolerated.  The  deter- 
mination of  the  metabolism  on  which  a  diabetic  subject  accomplishes 
work  is  of  great  therapeutic  importance,  since  the  work  that  is  a  benefit 
to  one  will  be  an  injury  to  another. 

In  many  cases  of  diabetes,  intercurrent  fever  tends  to  lower  the 
glucosuria,  by  increasing  the  combustion  of  glucose  just  as  in  the 
case  of  work.  In  other  cases,  especially  in  severe  diabetes,  the  con- 
verse is  true;  the  glucosuria  is  increased,  obviously  at  the  expense  of 
the  protein  metabolism;  and  the  acetone  bodies  may  be  increased, 
indicating  excessive  combustion  of  fat.  Any  further  speculations, 
based  upon  the  hypothesis  that  diabetes  is  a  disease  of  the  central 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         303 

nervous  system  and  localized  in  an  area  related  to  that  of  the  heat 
centres,  are  without  foundation. 

Toleration  of  Other  Sugars. — Levulose  and  lactose  (through  its  content 
of  galactose)  are  sometimes  tolerated  and  utilized  better  by  the  diabetic 
than  is  glucose.  This  is  a  fact  whose  meaning  is  not  at  all  clear.  The 
experiment  is  easily  made  either  by  giving  fructose  or  galactose  alone, 
or  by  giving  cane  sugar  or  milk  sugar.  In  the  event  of  a  positive  result, 
the  glucose  in  the  urine  will  not  be  increased  to  the  extent  noted  in  the 
case  of  the  ingestion  of  a  similar  amount  of  glucose.  According  to  our 
physiological  information,  fructose  and  galactose  are  in  the  mucosa 
of  the  intestine  and  in  the  liver  converted  into  glucose.  Since  the 
combustions  occur  in  the  muscles  and  not  in  the  liver,  and  since,  further- 
more, the  body  is  believed  to  burn  fructose  and  galactose  only  after 
conversion  into  glucose,  the  situation  is  entirely  unclear.  The  facts 
hold  for  diabetes  in  the  depancreatized  dog.  It  has  been<  suggested 
that  possibly  the  liver  can  form  glycogen  from  fructose  and  .galactose 
directly,  without  prior  conversion  into  glucose.  This  explanation  is 
not  improbable.  There  is  nothing  to  indicate  that  fructose  and  galac- 
tose cannot  be  polymerized  to  a  polysaccharid.  Indeed,  we  have  galac- 
tosans  in  nature,  though  they  do  not  much  resemble  starch  or  glycogen. 
All  the  natural  starches  yield  on  hydrolysis  only  glucose,  not  fructose 
or  galactose,  though  possibly  these  were  contained  in  the  polysaccharids 
and  converted  into  glucose  in  the  chemical  operations  of  hydrolysis. 
This  explanation  would  account  for  the  fact  that  following  the  inges- 
tion of  fructose  the  sugar  of  the  urine  is  not  increased.  It  would  also 
account  for  the  unfortunate  fact,  observed  in  the  treatment  of  diabetes, 
that  after  a  few  days  or  a  week,  the  regular  administration  of  fructose 
is  followed  by  rise  in  the  glucosuria  until  the  unit  of  input  is  recovered 
in  the  urine.  This,  under  the  explanation  suggested,  would  indicate 
that  the  toleration  for  fructose  lasts  only  so  long  as  the  body  can  con- 
vert it  into  glycogen  and  store  it  in  the  liver;  so  soon  as  the  storage 
capacity  for  glycogen  is  exceeded,  under  the  conditions  in  the  liver  that 
prevail  in  diabetes,  the  total  ingestion  of  fructose  reappears  in  the 
urine  in  the  form  of  glucose.  If  when  this  point  is  reached,  the  gluco- 
suria falls  coincidently  with  the  cessation  of  the  administration  of 
fructose,  it  is  clear  that  the  stored  glycogen  is  being  retained,  and  this 
is  of  undoubted  advantage  to  the  diabetic.  Whether  the  missing 
fructose  is  stored  as  glycogen  or  burned  at  the  time  could  be  deter- 
mined by  estimations  of  the  respiratory  quotient.  Variations  in  the 
toleration,  i.  e.,  utilization,  of  starches  of  different  derivation  are  also 
known.  Thus  the  starch  of  the  potato  is  supposed  to  burn  better  than 
that  of  maize.  There  is  no  doubt  of  one  fact,  diabetics  tolerate  oatmeal 
better  than  any  other  carbohydrate.  It  is  common  to  see  a  diabetic 
with  little  glucosuria  and  low  acidosis  on  100  grams  of  starch  per  day 
in  the  form  of  oatmeal,  when  50  grams  of  glucose  will  pass  almost 
quantitatively  into  the  urine.  This  toleration  is  not  invariable,  and 
it  is  often  lost.    For,  this  fact,  striking  as  it  is,  we  have  no  explanation. 


304  METABOLISM 

Pentoses  do  not  increase  the  glucosuria,  though  they  are  burned 
in  the  body.  This,  again,  is  not  now  comprehensible,  so  long  at  least 
as  we  hold  to  the  general  notion  that  pentose  is  only  burned  after 
conversion  into  hexoses.  For  one  pentose  in  particular,  rhamnose,  it 
has  been  shown  that  the  diabetic  can  burn  "up  to  100  grams  per  day. 
Curiously  enough,  however,  the  utilization  of  this  substance  seems  to 
provoke  an  exaggeration  of  the  protein  catabolism,  as  evidenced  by 
increase  in  the  glucose  and  nitrogen  in  the  urine. 

Glycogen  Theory. — Against  the  interpretation  of  the  defect  in  the 
combustion  of  glucose  in  diabetes  as  given  above,  stands  another 
hypothesis,  which,  since  its  promulgation  by  one  of  the  most  distin- 
guished students  of  diabetes,  deserves  adequate  statement  and  con- 
sideration. This  hypothesis  runs  to  the  effect  that  only  such  sugar 
can  be  burned  in  the  body  as  has  been  converted  into  glycogen  in  the 
body;  in  short,  it  is  the  glycogen  that  is  burned.  According  to  this 
view,  glycogen  must  be  incorporated  into  the  muscle  cell,  anchored  in 
its  protoplasm,  before  it  can  be  burned.  And  the  diabetic  is  held  to 
have  lost  the  power  of  anchoring  glycogen  in  its  muscle  cells.  In  favor 
of  this  hypothesis  are  the  facts  that  fructose  and  galactose  are,  for  a 
time  at  least,  better  tolerated  than  is  glucose;  and  the  unquestioned 
fact,  known  to  all  students  of  diabetes,  that  the  ability  to  store  and 
hold  glycogen  is  a  faculty  of  crucial  importance.  Reference  will  be 
made  later  to  this  importance  of  stored  glycogen  to  the  diabetic.  The 
question  is  not  as  to  these  facts;  it  is  as  to  whether  they  necessarily, 
or  even  most  naturally,  favor  the  hypothesis  stated.  There  is  in 
physiology  no  adequate  ground  for  the  assumption  that  the  muscles 
cannot  burn  sugar  directly  from  the  blood  stream  without  first  con- 
verting it  into  glycogen.  To  be  burned  it  must  be  first  returned  to  the 
state  of  glucose.  Taken  directly  from  the  blood  stream,  it  might  be 
urged,  it  is  in  the  free  state.  In  this  hypothesis,  on  the  other  hand, 
it  is  bound  to  protoplasm,  the  anchorage  of  the  glycogen  being 
assumed  to  hold  after  its  cleavage  into  glucose.  But  why  should  not 
the  protoplasm  bind  the  glucose  directly,  if  such  anchorage  be  held 
necessary?  Can  only  that  glucose  be  bound  that  was  bound  as  glycogen? 
Such  a  proposition  is  most  unusual.  If  an  animal  be  freed  of  glycogen 
by  starvation,  work  or  refrigeration,  it  maintains  its  body  heat  by 
combustion  of  fat  and  protein  and  has  the  corresponding  respiratory 
quotient.  If,  now,  to  such  an  animal  sugar  be  given,  in  a  very  short 
time  the  respiratory  quotient  rises,  indicating  that  this  sugar  is  being 
burned.  Is  it  to  be  assumed  that  this  sugar  carried  by  the  blood  to 
the  muscles  must  be  first  polymerized  to  glycogen  and  then  returned 
to  glucose  before  it  can  be  burned?  There  are  no  physiological  or 
chemical  data  to  warrant  this  assumption;  and  until  such  are  forth- 
coming, no  hypothesis  of  diabetes  can  be  founded  upon  it.  The  mere 
fact  that  the  storage  of  glycogen  is  of  great  benefit  to  the  diabetic 
organism  is  not  enough  to  warrant  the  physiological  dictum  that  sugar 
cannot  be  burned  directly  in  the  muscles,  but  only  after  conversion 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         305 

into  glycogen.  As  a  matter  of  fact,  defective  glycogenesis  and  defective 
combustion  of  glucose  do  not  always  run  parallel  in  diabetes. 

Lactic  Acid  Theory. — Quite  another  explanation  for  the  defective 
combustion  of  glucose  in  diabetes  centres  about  lactic  acid.  In  this 
it  is  assumed  that  in  the  muscles  glucose  is  split  into  lactic  acid,  which 
is  then  carried  to  the  liver  to  be  reconverted  into  glucose,  thus  main- 
taining a  vicious  circle.  In  the  interpretation  given  above,  it  was 
held  that  the  cleavage  to  lactic  acid  in  the  muscle  does  not  occur; 
did  it  occur  as  in  the  normal,  the  lactic  acid  would  be  burned.  The 
proposition  here  being  considered  is'  just  the  converse  of  this;  it  is 
assumed  that  the  glucose  is  split  to  lactic  acid,  but  instead  of  this 
being  burned  in  the  muscles,  it  is  returned  to  the  liver,  to  be  there 
converted  into  glucose  and  returned  to  the  circulation  and  muscles. 
This  would  naturally  result  in  hyperglucemia.  But  is  it  true  that 
the  diabetic  cannot  burn  lactic  acid?  No,  the  diabetic  can  burn  lactic 
acid.  The  hypothesis  is  surely  based  upon  a  misunderstanding  of 
the  mass  relations.  When  100  grams  of  a  lactate  are  given  to  a  severe 
case  of  diabetes,  it  reappears  in  part  as  sugar  in  the  urine.  When  it 
is  given  to  the  normal  individual,  we  may  be  sure  that  the  formation 
of  sugar  occurs  also,  but  it  does  not  become  visible  as  in  the  diabetic. 
A  heavy  ingestion  of  lactic  acid  so  increases  the  concentration  of  lactic 
acid  as  against  sugar  in  the  liver,  that  the  reversal  of  the  normal  reaction 
is  accomplished,  the  lactic  acid  is  converted  into  glucose.  This  occurs 
in  phloridzin  intoxication,  just  as  we  may  be  sure  it  occurs  in  the  normal. 
But  from  this  fact  to  assume  that  the  traces  of  lactic  acid  that  result 
in  each  moment  from  cleavage  of  glucose  in  metabolism  are  converted 
back  into  sugar,  is  entirely  arbitrary.  As  a  matter  of  fact,  less  lactic 
acid  is  present  in  the  muscles  in  diabetes  than  in  the  normal,  in  strict 
agreement  with  the  theory  that  the  defect  in  the  diabetic  consists  in 
inability  to  split  glucose  into  lactic  acid.  It  is  present  in  the  muscle 
only  as  a  transient  intermediary  stage,  and  from  this  lactic  acid,  in 
the  normal  and  in  the  diabetic,  we  may  be  sure  no  sugar  is  formed. 
For  such  a  postulated  inability  to  burn  lactic  acid  and  its  consequent 
conversion  into  glucose,  no  foundation  exists.  So  far  as  the  writer  is 
able  to  see,  there  is  but  one  condition  in  the  body  in  which  ingested 
lactic  acid,  under  proper  conditions  of  concentration,  cannot  be  utilized 
as  in  the  normal — in  hepatic  degeneration  of  the  type  seen  in  phosphorus 
poisoning  and  acute  yellow  atrophy. 

For  the  present,  therefore,  the  best  interpretation  of  the  failure  to 
burn  glucose  in  diabetes  rests  upon  the  proposition  that  on  account  of 
the  absence  of  the  internal  pancreatic  secretion  the  muscle  cell  has 
lost  the  power  of  cleavage  of  the  molecule  of  glucose  into  lactic  acid, 
or  some  previous  intermediary  stage,  whereby  the  oxidation  ferments 
are  denied  opportunity  of  action. 

Combustion  of  Substances  Other  than  Glucose. — The  faculty  of  com- 
bustion in  the  diabetic  has  been  tested  in  many  directions.  Citric 
acid,  tartaric  acid,  lactic  acid,  acetic  acid,  inosite,  mannite,  benzol, 
20 


306  METABOLISM 

d-gluconic  acid,  d-glucuronic  acid,  and  d-saccharic  acid  are  all  burned, 
in  every  way  as  in  the  normal.  Benzol  is  a  substance  of  difficult 
oxidation,  but  the  diabetic  burns  it  as  well  as  the  normal.  When 
one  contemplates  the  equation  for  d-gluconic,  d-glucuronic,  d-mucic, 
and  d-saccharic  acids,  all  combustible,  and  notes  that  one  contains 
the  aldehyd  group  and  another  the  terminal  alcoholic  group  intact, 
it  is  clear  that  the  defect  in  the  diabetic  cannot  lie  in  the  direction  of 
these  groups.  Beta-oxy-butyric  acid  the  diabetic  cannot  burn,  of 
which  more  later.  Some  diabetics  are  not  able  to  oxidize  dioxyphenyl- 
acetic  acid.  The  abnormalities  in  the  combustion  of  fat  and  protein 
will  be  discussed  under  the  appropriate  headings. 

Hyperglucemia. — In  all  cases  of  diabetes,  experimental  and  natural, 
varying  from  case  to  case,  an  excess  of  glucose  exists  in  the  blood.  This 
might  be  due  to  one  or  more  of  three  conditions: 

Non-combustion  of  glucose. 

Elevation  of  level  of  renal  retention. 

Overproduction  of  sugar. 

Overproduction  of  Sugar. — The  last  may  be  discussed  first  and  dis- 
missed. There  is  no  evidence  of  an  overproduction  of  sugar  in  diabetes. 
All  the  sugar  can  be  accounted  for  without  assuming  overproduction. 
From  carbohydrates  there  can  be  no  overproduction.  The  diabetic 
simply  eliminates  the  sugar  that  the  normal  body  burns.  Sugar  is 
formed  from  protein  in  the  diabetic  just  the  same  as  in  the  normal 
body.  Whether  this  function  is  facultatively  increased  in  diabetes, 
i.  e.,  whether  from  a  unit  of  protein  more  sugar  is  formed  than  under 
normal  conditions,  will  be  discussed  under  another  heading,  as  will 
also  the  question  whether  this  may  be  a  pathological  facultative  func- 
tion, operative  in  diabetes  but  not  in  health.  The  total  amount  of 
sugar  at  the  disposal  of  the  functions  of  the  body  is  surely  no  greater 
in  the  diabetic  than  in  health.  But  in  health  the  body  burns  it,  stores 
it  as  glycogen,  stores  it  as  fat  and  uses  it  to  save  the  protein  metabolism ; 
the  diabetic  does  none  of  these  in  the  normal  manner,  but  instead 
carries  it  in  the  blood  and  tissues  and  eliminates  it  in  the  urine.  There 
may  be  a  slight  excess  of  sugar  production  from  protein,  though  this 
is  doubtful.  But  in  the  sense  of  an  overproduction  of  sugar  beyond 
the  needs  of  or  utilization  in  the  body,  so  that  after  using  all  it  needs 
the  body  is  flooded  with  the  excess  of  sugar — no  such  thing  exists. 
The  normal  body  can  and  regularly  does  burn  far  more  sugar  than  any 
diabetic  organism  possesses.  The  hyperglucemia  is  due  to  deficient 
utilization  of  glucose,  possibly  to  elevation  in  the  level  of  renal  re- 
tention. 

The  glucose  concentration  of  normal  blood  seems  to  vary  from  6 
to  9  parts  in  the  ten  thousand.  In  the  lowest  values  seen  in  diabetes, 
15  to  25  parts  in  the  ten  thousand,  we  have  already  a  goodly  increase. 
From  this  up  values  are  recorded  to  over  100  parts  in  the  ten  thousand. 
It  is  greatly  to  be  desired  that  quantitative  analyses  of  the  blood  of 
diabetics  under  controlled  conditions  of  diet  be  done;  the  present 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         307 

data  are  too  fragmentary,  and  all  considerations  based  thereon  must 
be  subject  to  reservation. 

In  many  cases  there  is  a  proportional  relation  between  the  hyper- 
glucemia  and  the  glucosuria.  In  some  cases  the  proportionality  is 
better  noted  if  we  compare  with  the  blood  concentration  the  weight  of 
sugar  eliminated  rather  than  the  percentage.  In  many  cases,  however, 
no  such  proportionality  is  to  be  observed;  we  see  high  blood  concentra- 
tions with  low  glucosuria,  relatively  low  excess  in  the  blood  with  high 
glucosuria.  The  most  striking  exceptions  are  in  the  direction  of  hyper^ 
glucemia  with  slight  glucosuria.  Early  in  diabetes  we  may  find  little 
or  no  excess  in  the  blood,  with  active  elimination  by  the  kidneys.  In 
theory,  obviously,  this  ought  to  hold  if  the  kidneys  do  their  work; 
when  one  considers  how  much  sugar  the  kidneys  can  eliminate,  one  is 
led  to  wonder  why  in  many  cases  of  diabetes  the  kidneys  do  not  succeed 
in  keeping  the  glucose  of  the  blood  to  the  normal  level. 

In  some  cases  of  diabetes,  especially  in  early  stages,  the  glucosuria 
is  quite  independent  of  the  diet,  remaining  about  the  same  on  any 
reasonable  diet,  even  if  quite  free  of  carbohydrate.  Usually,  however, 
as  carbohydrate  is  added  to  a  protein-fat  diet,  the  glucose  in  the  urine 
rises  in  proportion;  and  as  the  ingested  amount  is  increased  absolutely 
more  and  more  of  the  amount  ingested  is  recovered,  until  finally,  all 
is  recovered  in  the  urine. 

When  a  diabetic  has  been  made  aglucosuric  by  diet,  as  often  succeeds, 
it  will  be  found  that  the  sugar  content  of  the  blood  is  lower  than  in  the 
same  case  on  carbohydrate  diet  with  glucosuria,  but  above  the  normal 
concentration  it  still  remains.  This  will  in  the  future  probably  prove 
to  be  a  prognostic  test  of  value,  as  in  this  way  the  disease  may  be 
unmasked. 

Elevation  of  Level  of  Renal  Retention. — When  one  contemplates  these 
relations,  one  cannot  but  feel  impressed  with  the  conviction  that  the 
kidney  ought  to  be  able  with  the  degree  of  hyperglucemia  present  in 
most  cases  of  diabetes,  to  keep  the  glucose  concentration  in  the  blood 
down  to  the  normal  level.  Thus  the  question  arises,  Is  not  the  renal 
level  of  retention  of  glucose  raised  in  diabetes,  conversely  to  phloridzin 
intoxication  in  which  it  is  lowered?  We  have  an  analogy  in  nephritis, 
in  which  the  level  of  retention  of  uric  acid  is  raised  much  above  the 
normal.  In  typical  advanced  diabetes,  it  may  be  stated  as  the  rule 
that  under  strict  conditions  of  diet  the  glucose  in  the  blood  is  higher 
than  it  should  be  in  consideration  of  the  degree  of  sugar  elimination 
in  the  urine  and  in  contrast  with  our  knowledge  of  what  the  kidneys 
can  accomplish  in  this  direction  under  other  conditions.  One  sees 
high  hyperglucemia  with  low  glucosuria.  What  else  does  this  mean 
than  a  renal  retention,  a  raised  threshold  value?  By  this  we  do  not 
mean  nephritis,  we  mean  simply  an  alteration  in  a  specific  function 
of  the  kidney,  an  increased  impermeability.  If  we  are  asked  to  explain 
what  is  meant  by  increased  renal  impermeability,  we  reply  by  asking 
for  a  definition  of  the  normal  permeability,  whereby  a  low  concentra- 


308  METABOLISM 

tion  of  glucose  in  the  blood  is  effectually  retained.  To  regard  the 
hyperglucemia  as  due  to  an  increase  in  the  sugar-binding  colloids  of 
the  blood  is  as  unfounded  as  to  regard  the  glucosuria  of  phloridzin 
intoxication  as  due  to  a  reduction  in  the  sugar-binding  colloids  of  the 
blood.  There  is  little  experimental  literature  on  the  subject,  though 
the  observations  stated  hold  for  pancreatic  diabetes  in  the  dog.  If  a 
depancreatized  dog  be  given  a  chromic  acid  nephritis,  the  glucosuria 
is  lowered.  It  is  also  a  common  experience  that  supervening  nephritis 
in  the  diabetic  is  often  associated  with  lowering  of  the  glucosuria. 
All  this,  however,  need  mean  nothing  directly  to  the  point  at  issue. 
The  question  must  be  settled  by  future  investigation.  The  matter 
is  of  practical  importance.  For  if  such  a  thing  occurs  as  increase  in 
the  impermeability  of  the  kidney  to  glucose,  the  glucosuria  loses  in 
part  its  indicative  value  in  diabetes;  if  one  could  reason  from  glucosuria 
to  glucemia,  our  conceptions  would  be  much  simpler  than  if  no  such 
relationship  is  to  be  postulated.  And  it  is  already  apparent  that  in 
many  cases  of  advanced  diabetes,  no  such  relationship  exists.  There  is 
in  the  blood  of  the  diabetic,  as  in  the  normal,  a  small  fraction  of  the 
blood  sugar  that  resists  fermentation;  and  this  fraction  is  absolutely 
increased  to  some  extent  in  diabetes.  When  the  blood  is  boiled  with 
weak  hydrochloric  acid,  the  total  blood  sugar  becomes  susceptible  to 
fermentation.  But  the  fraction  thus  bound  is  small,  and  no  argument 
can  be  based  upon  it  that  is  to  apply  to  the  whole  question  of  the 
foundation  of  hyperglucemia. 

Mixed  Melituria. — Pentose,  fructose,  maltose,  and  traces  of  dextrin 
and  even  of  glycogen  have  been  reported  in  the  urine  of  diabetics. 
While  there  can  be  no  doubt  of  the  reliability  of  some  of  the  observa- 
tions, it  is  certain  that  had  stricter  methods  of  identification  been 
employed  the  number  of  instances  would  be  much  less.  The  color 
methods  alone  ought  not  to  be  relied  upon  to  serve  as  criteria  of  fructose 
and  pentose.  Maltose  is  a  normal  sugar  in  the  blood  in  the  merest 
traces,  in  theory  at  least,  since  it  is  an  intermediary  stage  in  the  con- 
version of  glucose  into  glycogen,  and  vice  versa.  In  the  diabetic  its 
presence  may  be  reasonably  regarded  as  evidence  of  defective  glyco- 
genesis.  That  traces  of  glycogen  occur  in  the  urine  is  made  intelligible 
when  we  consider  the  fact  that  in  diabetes  the  renal  epithelium  is 
often  stuffed  with  glycogen.  Dextrin,  if  it  really  occurs,  would  have 
the  same  meaning  as  maltose. 

In  many  cases  of  the  reported  instances  of  fructosuria  in  diabetes, 
alimentary  or  hepatic  fructosuria  have  not  been  excluded.  In  some 
of  the  reported  cases,  however,  such  exclusion  has  been  rigidly  accom- 
plished. We  face  here  a  reversion  of  a  normal  reaction,  the  conversion 
of  glucose  into  fructose  instead  of  fructose  into  glucose.  Careful  analyses 
have  tended  to  indicate  that  fructose  may  occasionally  be  present 
in  the  blood  normally,  and  it  is,  therefore,  possible  that  in  its  appear- 
ance in  diabetes  we  are  dealing  simply  with  a  pathological  exaggera- 
tion of  a  normal  reaction.    It  is  in  the  severe  cases  of  the  disease  in 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         309 

particular  that  fructose  is  found  in  the  urine.  It  is  possible  to  assume 
that  a  mass  relation  between  glucose  and  fructose  holds  in  the  blood, 
with  the  station  of  equilibrium  very  much  in  favor  of  glucose.  At 
normal  concentration  of  glucose,  the  amount  of  fructose  would  be 
very  low,  below  the  level  of  analyses.  With  the  marked  hyperglucemia 
of  severe  diabetes,  the  operation  of  the  law  of  mass  action  would  result 
in  the  formation  of  larger  amounts  of  fructose,  so  that  its  presence  might 
become  evident.  Such  a  consideration,  based  upon  the  chemically 
well-known  ease  of  conversion  of  glucose  into  fructose  and  fructose 
into  glucose,  becomes  a  reasonable  interpretation  of  the  fructosuria 
of  diabetes.  In  a  certain  sense  the  sign  may  become  one  of  unfavor- 
able prognostic  meaning.  Viewed  in  this  manner,  there  is  nothing 
contradictory  in  the  toleration  of  fructose  by  the  diabetic  and  the 
occurrence  of  fructosuria  in  diabetes. 

With  regard  to  lactose  no  abnormal  relation  exists  in  diabetes.  The 
diabetic  mother  forms  milk  sugar  from  glucose  in  a  normal  manner. 
Nor  is  lactosuria  any  more  common  than  in  the  normal. 

Pentosuria  occurs  in  diabetes  so  rarely  that  it  is  a  question  whether 
it  has  been  more  than  a  coincidence.  For  the  identification  of  pentose 
sugars  in  the  urine,  more  rigid  methods  are  in  place  than  have  been 
usually  employed  in  the  past.  If  future  investigations  should  indicate 
that  pentosuria  does  occur  as  a  complication  of  diabetes,  we  will  have 
before  us  simply  another  disturbance  of  the  carbohydrate  metabolism; 
and  its  occurrence  in  the  diabetic  organism  will  be  no  more  strange 
than  is  its  occurrence  under  other  conditions,  of  which  we  know  so 
little.  When  the  chemical  meaning  of  pentosuria  of  idiopathic  type 
is  understood,  that  of  diabetes  will  probably  present  no  difficulties. 

Hepatic  Glycogenesis.— It  is  difficult  to  measure  the  hepatic  function 
of  conversion  of  sugar  into  glycogen  and  the  storage  of  the  latter, 
because  of  our  inability  to  control  hepatic  glycolysis.  We  can  always 
study  hepatic  glycolysis,  because  we  can  control  glycogenesis  by  fixing 
the  input.  Normal  for  each  individual  is  a  physiological  figure  for 
the  storage  of  glycogen  in  the  liver,  and  as  a  rule,  with  usual  diets  the 
body  operates  within  this  limit.  When  to  a  diabetic  dog  whose  liver 
(already  poor  in  glycogen)  has  been  freed  of  glycogen  by  starvation, 
glucose  is  given,  it  will  appear  in  the  urine  in  a  very  short  time.  This 
indicates  that  the  formation  of  glycogen  in  the  liver  is  defective,  unless 
the  function  of  glycolysis  operates  so  rapidly  that  the  glycogen  is  built 
down  to  sugar  as  fast  as  it  is  built  up  to  glycogen.  If  in  such  an  experi- 
ment the  respiratory  quotient  were  to  remain  constant  and  not  all 
of  the  ingested  sugar  were  recovered  in  the  urine,  we  would  know  that 
some  of  the  sugar  was  stored  as  glycogen;  but  we  would  not  be  in  a 
position  to  know  whether  deposition  occurred  in  the  liver  or  in  the 
muscles.  The  toleration  of  starch  when  contained  in  oatmeal  as  con- 
trasted with  the  toleration  of  starch  or  sugar  in  other  forms,  has  been 
usually  interpreted  to  rest  upon  variations  in  hepatic  glycogenesis. 
The  same  explanation  is  suggested  for  the  toleration  for  fructose  as 


310  METABOLISM 

against  glucose.  Since  the  glucose  formed  in  the  liver  from  glycogen, 
howsoever  derived,  is  always  the  same,  it  is  natural  to  localize  the  site 
of  toleration  of  oatmeal  in  the  liver.  While  the  data  are  largely  qualita- 
tive and  not  satisfactorily  conclusive,  we  may  provisionally  conclude 
that  insufficient  formation  of  glycogen  from  glucose  occurs  in  the  liver 
as  a  defect  in  diabetes.  This  opinion  is  solidified  by  indirect  evidence. 
The  liver  of  the  diabetic  is,  as  previously  stated,  very  poor  in  glycogen 
though  the  blood  that  drips  from  it  is  rich  in  sugar.  In  the  depan- 
creatized  dog,  the  liver  is  no  poorer  in  glycogen  during  starvation 
than  after  a  carbohydrate  meal.  At  the  same  time  it  must  be  confessed 
that  these  results  could  be  quite  as  well  explained  by  an  exaggeration 
of  glycolysis  associated  with  even  normal  glycogenesis.  The  equilib- 
rium is  obviously  disturbed,  and  this  is  all  the  more  striking  when 
the  hyperglucemia  is  considered.  But  such  a  disturbance  in  the  equilib- 
rium could  be  as  easily  the  result  alone  of  excessive  glycolysis  (which 
can  be  proved)  as  of  defective  glycogenesis. 

An  excess  of  glycogen  may  be  found  in  the  leukocytes  and  in  the 
renal  epithelium,  though  the  demonstration  has  been  usually  morpho- 
logical and  not  chemical.  If  this  be  true,  it  suggests  that  the  leuko- 
cytes and  the  renal  cells  form  glycogen  from  the  hyperglucemic  blood, 
an  illustration  of  the  law  of  mass  action. 

Hepatic  Glycolysis. — The  formation  of  glucose  from  glycogen  is 
unquestionably  excessive  in  diabetes.  Normally,  the  hepatic  regula- 
tion of  glycolysis  is  very  accurate,  no  hyperglucemia  occurs  no  matter 
how  little  or  how  great  the  combustion  of  sugar,  no  matter  how  much 
carbohydrate  the  diet  contains  up  to  the  storage  capacity  of  the  liver 
for  glycogen.  In  diabetes  the  conversion  of  glycogen  into  sugar  operates 
excessively,  so  that  the  sugar-holding,  or  more  properly  speaking 
glycogen-holding  power  of  the  liver  is  reduced  to  the  minimum.  The 
removal  of  the  pancreas  acts  as  directly  in  this  direction  as  does  the 
puncture  of  Bernard  and  almost  as  quickly.  Within  a  few  hours  after 
the  removal  of  the  pancreas  in  a  fasting  dog,  the  hyperglucemia  and 
glucosuria  appear,  and  in  a  surprisingly  short  time  the  liver  will  be 
found  poor  in  glycogen.  The  same  result  will  be  attained,  though  in 
less  time,  in  a  dog  in  full  carbohydrate  nutrition;  the  hyperglucemia 
and  glucosuria  appear  promptly,  but  more  time  will  be  required  to 
free  the  liver  of  glycogen.  This  defect  has  no  direct  relation  to  the 
inability  to  burn  sugar,  since  it  may  be  produced  by  the  puncture 
of  the  medulla  and  through  the  action  of  many  drugs,  without  the 
power  of  burning  sugar  being  in  the  least  disturbed.  The  pancreas, 
moreover,  has  a  direct  relation  to  the  hepatic  function  of  glycolysis, 
and  the  writer  does  not  believe  that  this  can  be  explained  as  the  result 
of  any  interference,  through  the  removal  of  nerve  fibers  in  the  extirpa- 
tion of  the  pancreas,  with  the  action  of  the  glycolytic  centre  in  the 
central  nervous  system.  How  the  removal  of  the  pancreas  results 
in  stimulation  of  the  glycolytic  centre  or  function  is  too  distant  a  con- 
jecture to  be  attempted.    One  might  obviously  assume  that  the  pancreas 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         311 

furnishes  a  substance  that  physiologically  represses  the  glycolytic 
centre  (in  somewhat  the  same  general  sense  as  the  vagi  repress  the 
heart  action),  but  that  is  an  explanation  after  the  fact.  Throughout 
the  course  of  diabetes  this  excessive  activity  of  the  glycolytic  function 
of  the  liver  is  in  evidence;  and  so  far  as  its  normal  role  in  the  regula- 
tion of  the  carbohydrate  metabolism  is  concerned,  the  liver  might  as 
well  be  absent.    It  is  certainly  of  little  use  to  the  diabetic. 

Glycogenesis  and  Glycolysis  in  the  Muscle. — The  muscles  of  the  diabetic 
are  poor  in  glycogen,  despite  the  fact  that  the  blood  is  excessively  rich 
in  glucose,  which  under  normal  conditions  would  result  in  the  forma- 
tion and  storage  of  large  amounts  of  glycogen.  The  renal  cells  that 
normally  contain  little  glycogen  are  in  diabetes  filled  with  it;  but  the 
muscle  cells,  whose  function  it  is  to  form  and  store  glycogen,  are  empty. 
So  far  as  we  are  able  to  determine,  the  fault  lies  rather  in  defective 
glycogenesis  than  in  excessive  glycolysis.  That  the  latter  exists,  how- 
ever, is  made  evident  by  the  rapidity  with  which  the  muscles  become 
poor  in  glycogen  after  extirpation  of  the  pancreas.  This  defect  in  the 
carbohydrate  metabolism  of  the  muscles,  all  the  more  striking  when 
the  hyperglucemia  is  recalled,  is  a  clear-cut  illustration  of  a  patho- 
logical alteration  in  a  station  of  equilibrium.  From  a  concentration  of 
glucose  as  much  as  tenfold  the  normal,  little  or  no  glycogen  is  formed. 
This  may  be  reasonably  interpreted  as  an  expression  of  defective  fer- 
ment action,  since  the  formation  of  glycogen  from  glucose  we  regard  as 
an  enzyme  reaction.  It  is  a  defect  of  grave  misfortune  to  the  diabetic 
organism.  Clinical  experience  leaves  little  doubt  of  the  truth  of  the 
dictum  that  the  lower  the  reserve  of  glycogen  in  the  diabetic,  the  nearer 
to  the  danger  line  is  he.  The  glycogen  seems  to  spare  the  fat  metab- 
olism and  acidosis  is  liable  to  arise  with  almost  explosive  violence  when 
the  depletion  of  the  store  of  glycogen  has  reduced  the  reserve  to  a  mini- 
mum. Many  an  unfortunate  diabetic  has,  by  excessive  carbohydrate 
starvation,  been  brought  to  the  danger  line  of  such  an  acidosis,  not 
infrequently  to  succumb.  To  fully  appreciate  the  value  of  the  glycogen 
stores  to  the  diabetic,  one  does  not  need,  however,  to  subscribe  to  the 
hypothesis  that  fat  can  only  be  burned  with  sugar,  or  believe  that 
glucose  is  only  burned  after  conversion  into  glycogen.  Future  investiga- 
tions must  show  the  exact  relations. 

The  Formation  of  Fat  from  Glucose. — Not  only  is  the  formation  of 
glycogen,  the  proximate  state  of  storage  of  sugar,  defective  in  diabetes; 
the  formation  of  fat,  the  ultimate  state  of  storage,  is  also  defective. 
In  the  normal  body,  hyperglucemia  leads  first  to  formation  of  glycogen, 
then  to  formation  of  fat;  in  the  typical  instance  of  diabetes,  hyper- 
glucemia is  followed  by  neither.  This  again  is  a  disturbance  of  the 
normal  state  of  equilibrium,  since  with  such  a  hyperglucemia  as  the 
diabetic  possesses,  the  formation  of  fat  from  sugar  ought  to  be  greatly 
increased,  instead  of  which  it  is  decreased.  Were  this  function  in  a 
normal  state  (even  though  no  sugar  were  burned),  the  body  would 
be  able  to  convert  into  fat  all  the  sugar  formed  from  protein,  and  this 


312  METABOLISM 

would  thus  be  saved  to  the  organism.  Under  such  circumstances, 
even  though  sugar  could  not  be  burned  directly,  it  would  be  burned 
via  fat  and  the  hyperglucemia  and  glucosuria  of  the  diabetic  would 
not  exist.  So  far  as  can  be  seen,  this  is  a  direct  and  fundamental  defect 
in  the  function  of  lipogenesis,  and  cannot  be  grounded  upon  any  known 
defect  in  the  sugar  catabolism.  Nor  can  it  be  attributed  to  the  lack 
of  glycogen,  since  the  fat  is  surely  formed  from  glucose  and  not  from 
glycogen.  Not  all  cases  of  diabetes,  even  severe  ones,  display  this 
defect.  Occasionally,  one  sees  severe  diabetes  with  obesity — just  what 
would  be  expected  with  cessation  of  the  function  of  sugar  combustion 
and  retention  of  the  power  of  lipogenesis.  Even  such  cases,  however, 
are  apt,  after  a  time,  to  become  emaciated  and  to  lose  their  power  of 
forming  fat. 

A  possible  chemical  explanation  of  the  inability  of  the  diabetic  to 
form  fat  from  sugar  lies  in  the  behavior  of  butyric  acid  in  the  diabetic 
metabolism.  As  will  be  stated  in  the  chapter  devoted  to  the  metab- 
olism of  fat,  according  to  our  present  conceptions  when  a  fatty  acid  is 
burned  it  is  built  down  in  regular  stages  to  butyric  acid,  and  through 
this  to  final  oxidation.  Now  in  the  diabetic  this  butyric  acid  is  oxidized 
to  beta-oxy-butyric  acid,  from  which  proceed  diacetic  acid  and  acetone. 
In  the  formation  of  fat  from  sugar,  it  would  seem  possible  that  butyric 
acid  might  be  the  stage  to  which  the  transfer  is  made  from  the  sugar 
to  the  fatty  acid.  This  we  may  provisionally  sketch  as  follows:  glucose 
-»  lactic  acid  — >  acetic  aldehyd  -*  beta-oxy-butyric  aldehyd  ->  butyric 
acid  -»  higher  fatty  acid  plus  glycerin  — >  fat.  Since  now  in  diabetes 
the  butyric  acid  derived  from  catabolized  fat  is  not  treated  in  the  normal 
manner,  there  is  no  reason  why  the  butyric  acid  derived  from  glucose 
should  have  any  different  fate.  We  might,  therefore,  assume  that  it 
is  simply  joined  to  the  acetone  group,  instead  of  being  converted  into 
fat  as  in  the  normal.  Not  only  would  this  serve  to  explain  the  inability 
of  the  diabetic  organism  to  form  fat  from  sugar,  it  would  also  constitute 
an  additional  source  for  the  acetone  bodies.  This  is  merely  an  hypo- 
thesis, to  be  tested  in  the  future.  The  fact  that  the  administration 
of  sugar  is  usually  followed  by  reduction  in  the  acidosis  is  unfavorable 
to  the  hypothesis,  since  with  the  concentration  of  glucose  in  the  circula- 
tion increased,  the  formation  of  butyric  acid  ought  in  accordance  with 
the  law  of  mass  action  to  be  increased.  Favorable  to  the  hypothesis 
is  the  fact  that  it  is  precisely  in  the  diabetic  with  acidosis  that  we  see 
most  marked  the  failure  of  the  function  of  the  formation  of  fat  from 
sugar.  Directly  unfavorable  to  the  hypothesis  is  the  fact  that  the 
scheme  demands  the  cleavage  of  glucose  into  lactic  acid,  whereas  pre- 
cisely in  the  inability  of  the  diabetic  body  to  form  lactic  acid  from  glucose 
lies  apparently  the  fundamental  defect  of  the  metabolism  in  diabetes. 

It  is  possible  that  some  cases  of  pathological  obesity  are  due  to 
defective  combustion  of  sugar  with  retention  of  the  function  of  lipo- 
genesis, i.  e.,  are  masked  diabetes.  Some  clinical  cases  of  diabetes 
supervene   on    sudden,   unnatural    obesity,    and    this   might    be    the 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES        313 

unmasking  of  the  disease.  It  is,  however,  conceivable  that  such  cases 
in  later  life  might  remain  stationary,  the  obesity  masking  the  mild 
diabetes  completely.  A  determination  of  the  respiratory  quotient 
would,  however,  serve  to  uncover  such  a  case,  since  it  would  yield  a 
low  quotient,  indicating  the  lack  of  combustion  of  sugar. 

The  Origin  of  Glucose  in  Diabetes. — When  the  normal  body  fasts 
or  is  placed  upon  a  protein-fat  diet,  the  sugar  metabolism  becomes, 
so  to  speak,  quiescent;  under  identical  conditions  in  the  diabetic, 
glucose  continues  to  be  eliminated,  and  often  in  large  amounts.  Whence 
is  this  glucose  derived?  This  cardinal  problem  in  diabetes  has  been 
brought  much  nearer  solution  in  the  last  half  dozen  years.  This  brings 
us  to  the  consideration  of  the  protein  metabolism  in  diabetes. 

The  Protein  Metabolism  in  Diabetes. — The  protein  metabolism  may 
be  said  to  be  always  exaggerated  in  diabetes.  This  is  strikingly  shown 
in  the  fact  that  the  nitrogen  in  the  urine  of  the  starving  diabetic  is 
from  two  to  five  times  as  much  as  in  the  starving  normal  individual. 
The  nitrogen  balance  is  usually  maintained,  but  only  by  the  ingestion 
of  masses  of  protein  in  excess  of  those  normally  required  to  maintain 
such  an  equilibrium.  The  mere  fact  that  the  diabetic  loses  in  large 
part  the  carbon  of  the  protein  molecule,  as  will  be  later  discussed, 
would  serve  to  explain  this.  If,  however,  the  average  diabetic  be 
placed  upon  a  fat-protein  diet,  it  will  be  found  that  the  nitrogen  balance 
will  be  reached  on  the  same  input  of  protein  needed  by  the  normal 
individual.  But  the  adaptation  is  much  lessened.  If  the  fat  be  held 
high  and  the  protein  reduced,  the  reduction  in  protein  input  will  be 
followed  by  a  nitrogen  defect  more  quickly  in  the  diabetic  than  in  the 
normal.  In  the  normal  body  under  such  circumstances,  the  glucose 
that  is  formed  from  the  catabolized  protein  spares  protein,  as  does 
also  the  fat;  in  the  diabetic,  this  sugar  is  largely  lost,  and  the  sparing 
power  of  fat  for  protein  is  reduced  also.  Many  cases  of  severe  diabetes, 
with  the  free  use  of  fat  will  maintain  a  nitrogenous  equilibrium  on  a 
relatively  low  protein  input,  no  more  than  10  grams  of  nitrogen  per 
day.  But  it  is  inclined  to  be  precarious,  and  often  cannot  be  main- 
tained. This  fact  is  of  importance,  since  in  periods  it  is  desirable  to 
reduce  the  glucosuria  by  reduction  of  the  protein  (source  of  the  sugar), 
while  at  the  same  time  the  nitrogen  equilibrium  ought  not  to  be  dis- 
turbed. It  is  indeed  possible,  for  periods  at  least,  to  retain  nitrogen 
in  the  diabetic  body,  though  this  is  usually  not  a  true  retention  in  the 
sense  of  tissue  building,  but  a  spurious  retention,  to  be  lost  again  when 
the  diet  is  reduced.  Apparently  a  body  cannot  build  flesh  unless  it 
can  store  glycogen.  The  average  diabetic  will  ingest  with  200  to  250 
grams  of  fat  (if  it  can  be  ingested),  125  to  150  grams  of  protein  per 
day;  and  the  metabolism  apart  from  the  loss  of  the  sugar  derived  from 
the  protein  is  not  then  greatly  different  from  the  normal. 

The  exaggeration  of  the  protein  catabolism  seems  more  marked  in 
the  pancreatic  diabetes  of  the  dog  than  in  man,  for  which  reason,  as 
well  as  for  others,  we  term  the  experimental  disease  in  the  dog  a  com- 


314  METABOLISM 

plete  diabetes.  The  average  nitrogen  output  of  normal  individuals 
in  fasting  runs  from  4  to  6  milligrams  per  kilo  per  hour.  In  diabetes 
the  fluctuations  are  much  greater  than  in  the  normal,  and  the  values 
run  up  to  10  milligrams  per  kilo  per  hour.  The  fluctuations  in  time 
observed  in  diabetes  are  of  especial  interest.  The  curve  of  nitrogen 
output  always  follows  sometime  behind  that  of  the  sugar,  as  in  the 
phloridzinized  dog.  But  the  irregularities  in  the  flow  of  the  nitrogen 
output  suggest  at  least  that  the  inner  mechanism  of  the  disintegration 
of  protein  is  disturbed.  Extreme  cases  of  diabetes  will  give  much 
larger  eliminations  of  nitrogen  than  the  figures  just  given,  approaching 
those  of  the  depancreatized  diabetic  dog.  The  administration  of  glucose 
has  no  sparing  power  for  protein  in  severe  diabetes,  even  when  some 
of  the  administered  sugar  is  not  recovered  in  the  urine.  Normally, 
the  combustion  of  glucose  spares  both  protein  and  fat  and  the  saving 
power  for  fat  is  total  in  the  sense  that  the  body  will  burn  no  fat  if  a 
sufficient  amount  of  sugar  be  available.  In  diabetes  the  saving  power 
of  sugar  for  fat  is  still  shown  in  the  action  of  sugar  upon  the  acidosis. 
This  is  retained  much  longer  than  is  the  saving  power  for  protein. 
So  long  as  the  body  cannot  burn  the  sugar  formed  from  protein,  the 
ingestion  of  further  sugar  would  be  expected  to  have  no  saving  power 
for  protein. 

In  diabetic  coma  amino-acids  appear  in  the  urine,  indicating  that 
the  catabolism  of  protein  in  part  is  not  completed  to  the  normal  end 
products. 

When  in  severe  diabetes,  the  power  of  burning  sugar  is  reduced 
to  the  lowest  level,  and  when  also  the  power  of  burning  fat  is  markedly 
disturbed,  the  maintenance  of  nitrogenous  equilibrium  is  only  possible 
through  the  ingestion  of  greatly  increased  amounts  of  protein.  It 
may  require  protein  representing  25  or  30  grams  of  nitrogen,  or  even 
more,  to  maintain  the  nitrogen  balance.  Under  such  circumstances, 
and  especially  in  the  absence  of  the  protein-saving  power  of  sugar, 
it  may  not  be  possible,  even  with  the  most  maximum  ingestions  of 
protein,  to  retain  nitrogen  at  all,  i.  e.,  under  no  circumstances  can 
flesh  be  restored.  In  a  certain  sense,  the  plane  upon  which  a  diabetic 
can  maintain  a  nitrogenous  equilibrium  is  an  indication  of  the  severity 
of  the  disease — though  many  exceptions  to  the  rule  occur.  Not  only 
is  the  demand  for  a  large  protein  ingestion  to  maintain  the  nitrogenous 
equilibrium  an  indication  of  the  severity  of  the  metabolic  abnormality, 
the  large  amounts  of  glucose  derived  therefrom  exaggerate  the  hyper- 
glucemia  and  glucosuria.  And  this  hyperglucemia  is  directly  an  injury 
to  the  tissues. 

In  this  presentation  of  the  facts,  it  has  been  obviously  assumed 
that  the  exaggeration  of  the  protein  catabolism,  no  matter  how  pro- 
nounced, is  merely  secondary  to  the  states  of  the  catabolism  of  glucose 
and  fat  and  not  primary.  That  the  diabetic  is  hard  put  to  for  fuel  to 
maintain  the  body  temperature  is  obvious.  But  is  this  dire  necessity 
the  sole  causation  of  the  exaggerated  catabolism  of  protein?     Or  is 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES        315 

there,  as  in  phosphorus  poisoning,  a  primary  autolytic  exaggeration 
of  the  protein  catabolism?  When  one  contemplates  the  muscular 
wasting  of  a  severe  case  of  diabetes,  the  thought  of  a  primary  toxic 
proteolysis  comes  strikingly  to  mind.  The  hyperglucemia  is  toxic 
to  the  tissues;  experiments  on  the  action  of  sugar  solutions  in  the 
biological  laboratory  leave  little  doubt  of  this.  The  cessation,  or 
rather  reduction,  in  the  muscles  of  the  function  of  combustion  of 
glucose  would  produce  conditions  tending  to  atrophy,  entirely  inde- 
pendent of  the  carbohydrate  and  fat  metabolism.  When  the  diabetic 
suffers  from  gangrene  or  septic  infection,  then  surely  a  toxic  cytolysis 
is  superadded  to  the  metabolic  exaggeration  of  protein  catabolism. 
But  direct  experiments  with  the  nitrogen  equilibrium  under  controlled 
conditions  have  never  given  figures  that  warrant  the  interpretation 
that  in  uncomplicated  diabetes  a  toxic  exaggeration  of  the  protein 
catabolism  exists,  primary  in  type.  Further  investigations  may  reverse 
the  present,  not  very  extensive,  data.  But  for  the  present,  the  exaggera- 
tion of  the  protein  catabolism  must  be  regarded  as  secondary,  so  to 
speak  compensatory,  and  not  primary.  This  conclusion  carries  with 
it,  obviously,  the  contradiction  of  the  hypothesis  of  a  primary  over- 
production of  sugar  as  a  factor  in  diabetes,  at  least  so  far  as  the  protein 
source  of  the  glucose  is  concerned. 

The  case  may  be  different  in  diabetic  coma,  of  which  no  investiga- 
tions have  been  made,  if,  indeed,  exact  investigations  are  possible.  Here 
we  are  concerned  with  an  acute  auto-intoxication,  which  might  easily 
be  assumed  to  carry  an  exaggeration  of  protein  catabolism  in  its  wake. 

The  Formation  of  Glucose  from  Protein. — It  will  be  necessary  in  order 
to  discuss  this  very  important  phase  of  the  metabolism  of  diabetes  to 
anticipate  the  consideration  of  the  qualitative  processes  in  the  catab- 
olism of  protein.  When  the  molecule  of  protein  is  hydrolyzed  in  the 
metabolism,  the  amino-acids  may  be  subjected  to  one  of  two  main 
chemical  procedures;  the  amino-acid  may  be  deaminated,  the  nitrogen 
converted  into  ammonia  (urea),  and  the  fatty  acids  burned;  or  the 
carbonous  fraction  of  the  amino-acids  may  be  converted  into  glucose, 
and  the  nitrogen  converted  as  before  into  ammonia  (urea).  In  the 
opinion  of  the  writer,  both  processes  occur  side  by  side  in  the  body. 
The  subject  is  one  very  difficult  of  quantitative  treatment,  since  the 
conditions  surrounding  the  necessarily  prolonged  experimentations 
resist  control  and  are  not  susceptible  of  unequivocal  interpretation. 
It  may  be  stated  here  that  isolated  experiments  with  different  amino- 
acids  have  indicated  that  in  the  liver  glucose  is  formed  from  them; 
and  viewed  as  a  total  process  in  the  normal  animal  metabolism,  glucose 
is  formed  from  catabolized  protein.  For  the  discussion  of  the  state 
of  affairs  in  diabetes,  it  is  not  now  whether  glucose  be  formed  from 
protein,  but  how  much  glucose  is  formed  from  protein.  Assuming  55 
per  cent,  as  the  maximum  content  of  carbon  in  the  protein  molecule, 
since  four  parts  of  carbon  corresponds  to  ten  parts  of  glucose,  it  is 
obvious  that  were  all  the  carbon  in  the  molecule  of  protein  converted 


316  METABOLISM 

into  glucose,  1  gram  of  protein  would  yield  1.4  gram  of  glucose,  and 
the  ratio  of  the  nitrogen  of  the  protein  to  the  glucose  derivable  from  it 
would  be  1  :  8.  Were  all  the  carbon  of  the  molecule  of  protein  converted 
into  sugar,  this  would  leave  the  nitrogen,  or  ammonia,  without  carbon 
to  form  urea.  While  it  is  true  that  the  ammonia  of  the  protein  catab- 
olism  would  combine  with  the  C02  of  the  blood  to  form  ammonium 
carbonate,  to  be  converted  into  urea,  yet  it  has  always  seemed  natural 
to  assume  that  the  carbon  of  urea  like  the  nitrogen  was  derived  from 
the  molecule  of  protein  directly.  If  this  be  true,  then  the  available 
carbon  in  the  molecule  of  protein  would  form  1.3  grams  of  sugar;  and 
the  glucose  :  nitrogen  ratio  would  be  7.8  :  1.  So  much  for  the  quantita- 
tive possibilities.  Now  the  best  experimental  data  indicate  that  in 
the  catabolism  of  protein  the  glucose  :  nitrogen  ration  is  under  4.5  :  1. 
This  means  that  from  1  gram  of  protein  0.75  gram  of  glucose  is  formed. 
The  remainder  of  the  carbon  must  be  burned  directly,  without  con- 
version into  sugar.  On  this  basis  of  reasoning,  if  a  diabetic  body  had 
lost  the  power  of  burning  and  storing  glucose  entirely,  all  the  sugar 
formed  from  protein  would  be  recovered  in  the  urine.  And  if  the 
animal  were  on  a  protein-fat  diet,  free  of  preformed  carbohydrate,  the 
urine  should  contain  4.5  grams  of  glucose  to  every  gram  of  nitrogen. 
If  under  controlled  conditions,  other  things  being  equal,  less  glucose 
were  recovered  in  the  urine,  it  would  be  proper  to  infer  that  the  differ- 
ence had  been  burned  or  stored.  It  is  clear,  therefore,  that  if  the 
simple  relation  stated  holds  for  the  interpretation  of  the  glucose: 
nitrogen  ratio,  this  should  be  of  determining  importance  in  the  study 
of  diabetes. 

When,  however,  we  come  to  inspect  carefully  the  glucose: nitrogen 
ratio,  analyse  the  conditions  surrounding  it  and  measure  the  controls 
that  may  be  experimentally  maintained  in  its  determination,  it  will 
become  clear  that  no  such  dependence  as  above  suggested  can  be  placed 
on  it.  The  exaggerated  importance  placed  on  this  ratio  in  some  schools 
of  physiology  is  in  no  way  better  illustrated  than  in  the  fact  that  the 
ratio  is  often  calculated  to  the  second  place  of  decimals,  which  is  un- 
warranted by  the  conditions  of  the  investigation.  What  are  the  condi- 
tions that  are  presupposed  in  the  determination  of  this  ratio  in  the 
study  of  diabetes  ? 

(a)  It  is  assumed  that  the  diabetic  does  not  store  carbohydrate 
at  all.  This  assumption  is  in  most  cases  of  diabetes  unwarranted. 
Many  cases  are  able,  in  some  stages  of  the  disease  at  least,  to  store 
such  amounts  of  glycogen  as  to  modify  the  ratio  to  quite  an  extent. 
The  longer  the  period  of  observation,  the  less  the  error  liable  to  lie  in 
this  assumption. 

(6)  It  is  assumed  that  the  diabetic  does  not  store  nitrogen.  This 
also  is  unwarranted,  in  many  cases  of  diabetes  at  least,  and  for  rather 
long  periods  of  time.  Estimations  of  the  nitrogen  output  should  always 
be  accompanied  by  estimations  of  the  input.  And  to  make  the  results 
certain  the  observations  should  be  extended  over  many  days.     The 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         317 

calculation  of  the  ratio  on  the  basis  of  a  single  day's  measurement  of 
the  nitrogen  and  glucose  of  the  urine  may  lead  to  grave  error.  A  man 
on  a  fixed  nitrogen  input  of  15  grams  per  day  may  exhibit  fluctuations 
in  the  output  of  as  high  as  3  or  4  grams  per  day,  the  retention  of  one 
day  being  followed  by  a  sweeping  out  on  the  day  or  days  following. 
The  influence  of  this  behavior  on  the  part  of  the  nitrogen  metabolism 
(observable  in  health),  may  be  shown  in  a  simple  calculation:  Let 
it  be  assumed  that  on  a  fixed  protein-fat  diet,  the  sugar  of  the  urine 
was  50  grams,  the  nitrogen  input  15  grams.  On  one  day  the  nitrogen 
output  might  be  13  grams,  on  the  following  day  17  grams.  The  G  :  N 
ratio  for  the  two  days  would  be  3.8  and  2.9  :  1.  Now  such  variations 
in  the  nitrogen  output  are  common.  They  indicate  how  useless  it 
is  to  calculate  the  ratio  into  the  second  place  in  decimals;  and  how 
much  more  representative  the  ratio  would  be  if  taken  in  periods  of  a 
week,  with  daily  estimation  of  the  input  and  the  nitrogen  of  the  stools. 
It  is  known  that  the  sugar  appears  in  the  urine  long  before  the  nitrogen 
of  the  protein  from  which  it  was  derived ;  and  it  has  been  rightly  insisted 
upon  that  the  collection  of  urine  should  last  at  least  twelve  hours 
after  the  last  meal  was  taken,  i.  e.,  the  day  for  the  purpose  of  the 
collection  of  urine  should  last  until  the  second  morning.  But  this, 
while  correct  and  in  the  right  direction,  is  not  enough.  The  G  :  N 
ratio  should  be  determined  in  periods  of  days,  the  more  the  better;  and 
the  nitrogen  balance  for  the  period  should  be  determined.  Many  of  the 
notorious  fluctuations  in  the  G  :  N  ratio  reported  in  clinical  diabetes 
have  been  undoubtedly  due  to  brevity  of  the  time  of  observation. 

(c)  It  is  assumed  that  all  the  glucose  in  the  urine  comes  from  the 
diet,  and  that  none  is  derived  from  stored  glycogen.  This  assumption 
is  in  many  cases  of  diabetes  entirely  unwarranted;  in  severe  and  pro- 
longed cases  on  the  other  hand,  it  is  substantially  correct. 

(d)  It  is  assumed,  in  certain  quarters  at  least,  that  the  body  is  burn- 
ing no  glucose.  This  assumption  is  unwarranted  in  all  cases;  as  will 
later  be  detailed  under  the  discussion  of  the  respiratory  quotient,  it 
is  quite  certain  that  there  is  some  combustion  of  glucose  in  nearly  all 
cases  of  diabetes  except  in  terminal  coma,  and  often  a  goodly  utiliza- 
tion indeed.  Obviously  the  real  ratio  is  commonly  higher  than  the 
observed  ratio,  as  a  rule,  higher  in  degree  directly  proportional  to  the 
severity  of  the  case. 

(e)  It  has  been  assumed  that  protein  is  protein  in  the  diet,  so  far 
as  the  sugar-forming  capacity  is  concerned;  and  that,  therefore,  we 
need  only  calculate  from  the  nitrogen  output,  without  inquiring  where 

•it  came  from.  Now  this  is  incorrect,  proteins  do  not  yield  glucose  in 
any  fixed  relation  to  the  nitrogen;  100  grams  of  nitrogen  in  the  forms 
of  gelatin,  casein,  and  edestin,  for  example,  would  not  yield,  under 
the  terms  of  a  perfect  experiment,  the  same  amounts  of  glucose.  This 
is  due,  as  will  be  elsewhere  explained,  to  the  fact  that  the  different 
amino-acids  are  not  equally  available  as  sources  of  glucose,  and  the 
different  proteins  contain  different  amounts  of  the   several  amino- 


318  METABOLISM 

acids.  It  is,  therefore,  necessary  to  bear  a  caution  in  this  regard,  though 
to  date  we  do  not  know  how  to  classify  the  proteins  even  approximately 
on  the  basis  of  their  glucose-yielding  properties.  Naturally,  it  is  neces- 
sary to  employ  in  the  diet  a  protein  free,  or  nearly  free,  of  preformed 
carbohydrate,  casein  and  codfish  being  the  most  available. 

(/)  It  is  assumed  that  there  is  no  further  source  of  glucose  than  the 
protein.  Upon  no  warrant  is  the  glycerol  of  the  fat  undergoing  com- 
bustion to  be  disregarded.  That  this  glycerol  is  available  for  conversion 
into  glucose  is  chemically  certain;  that  the  glycerol  of  the  body  is 
converted  into  sugar  and  burned  as  such,  is  highly  probable.  The 
amounts  involved  would  not  be  negligible.  Fat  contains  10  per  cent, 
of  glycerol;  200  grams  of  fat  are  a  usual  ration  of  fat  for  a  diabetic. 
From  the  glycerol  of  this  amount  of  fat  the  body  could  form  20  grams 
of  glucose.  When  it  is  recalled  that  few  diabetics,  on  a  protein-fat 
regimen,  eliminate  over  50  to  75  grams  of  sugar,  the  error  introduced 
into  the  interpretation  of  the  G  :  N  ratio  by  20  grams  of  glucose  formed 
from  glycerol  is  obvious. 

Glucose-nitrogen  Ratio. — Coming  now  to  the  use  that  has  been  made 
of  the  glucose-nitrogen  ratio  in  the  development  of  the  theories  of 
diabetes,  we  meet  with  a  most  unsatisfactory  situation.  On  the  one 
hand,  it  having  been  assumed  that  the  diabetic  burns  no  sugar,  the 
ratio  has  been  used  as  an  index  of  the  formation  of  glucose  from  protein. 
On  the  other  hand,  using  the  current  physiological  ratio  (4.5  :  1),  as 
representing  the  potential  formation  of  glucose  from  protein,  the  ratio 
found  clinically  has  been  used  as  an  index  of  the  loss  of  the  power  of 
burned  sugar.  To  prove  each  point  it  is  necessary  to  assume  the  other. 
It  is  not  possible  to  assume  that  the  glucose  :  nitrogen  ratio  represents 
accurately  the  relation  of  the  formation  of  glucose  from  the  protein 
undergoing  catabolism.  It  is  possible,  but  only  in  a  general  sense,  to 
measure  the  combustion  of  glucose  in  the  body  by  the  determination 
of  the  glucose :  nitrogen  ratio,  they  being  held  roughly  to  be  inversely 
proportional. 

One  additional  fact  tends  to  invalidate  still  more  the  conclusions 
drawn  from  this  ratio.  When  the  body  of  the  diabetic,  in  partial  or 
complete  fasting,  maintains  its  body  heat  by  the  combustion  of  its 
own  protein  and  fat,  it  forms  from  the  unit  of  its  own  protein  less 
glucose  than  from  a  similar  unit  of  foreign  protein  ingested  as  food. 
This  fact  alone  makes  it  clear  that  the  ratio  currently  used  in  physiology 
to  represent  the  amount  of  sugar  formed  from  protein  (4.4  :  1)  cannot 
be  employed  as  the  rigid  basis  of  measurement  in  diabetes. 

In  the  dog  (in  whom  the  physiological  ratio  of  4.4  :  1  was  deter- 
mined), the  ratio  in  pancreatic  diabetes  will  usually  be  found  about 
2.8  :  1  on  an  average.  In  some  dogs  higher  ratios  will  be  found,  in 
other  animals  lower  ratios.  But  by  comparison  with  the  ratios  obtained 
in  cases  of  human  diabetes,  the  ratios  observed  in  the  dog  are  very 
constant.  In  phloridzin  intoxication  in  dogs  the  most  common  ratio 
is  about  3.7  :  1,  though  it  may  be  as  high  as  the  normal  ratio  for  the 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         319 

dog  or  even  higher,  up  to  5  :  1,  the  highest  figures  usually  only  during 
the  first  few  days.  The  high  glucose :  nitrogen  ratio  of  the  first  few 
days  of  a  phloridzin  intoxication  has  been  commonly  attributed  to  the 
washing  out  of  the  stored  carbohydrate.  This  may  be  true  in  some 
instances.  But  in  other  carefully  studied  instances,  the  glucose  output 
was  constant  from  the  first  day,  and  the  fall  in  ratio  on  the  third  or  fourth 
day  was  due  to  a  rise  in  the  elimination  of  nitrogen.  When  we  consider 
the  great  difficulties  that  attend  the  fixing  of  the  physiological  ratio, 
this  we  may  set  at  5  :  1  as  a  maximum.  From  this  it  may  be  inferred 
that  the  diabetic  dog  eliminates  on  an  average  only  a  little  over  half 
the  glucose  formed  from  protein;  the  balance  must  have  been  stored 
or  burned.  The  phloridzinized  dog  apparently  eliminates  a  larger 
proportion  of  the  sugar  formed  from  protein  than  does  the  diabetic 
dog,  in  the  usual  case  eliminating  over  three-quarters  of  the  glucose 
formed.  It  is  most  suggestive  to  note  that  in  diabetes  in  the  dog 
and  in  phloridzin  intoxication  in  the  dog,  the  ratio  observed  after  the 
first  days  is  never  higher  than  the  ratio  determined  physiologically  for 
the  same  animal.  Assuming,  therefore,  that  in  the  physiology  of  the 
dog,  the  body  normally  forms  five  units  of  glucose  from  the  protein 
containing  one  unit  of  nitrogen  (1  gram  protein  =  0.8  gram  glucose), 
it  is  clear  that  if  the  control  of  the  experiments  be  complete,  so  long 
as  we  infer  that  the  faculty  of  formation  of  glucose  from  protein  is  a 
constant,  it  follows  that  the  diabetic  dog,  as  a  rule,  retains  the  power 
of  burning  from  a  third  to  a  half  of  the  sugar  produced  from  the  physio- 
logical ration  of  protein,  while  the  phloridzinized  dog,  whose  powers 
of  combustion  of  glucose  are  normal,  burns  less  simply  because  the 
glucose  is  swept  out  of  the  system  before  the  muscles  have  opportunity 
to  burn  it.  When  we  limit  our  inductions  to  the  careful  experiments 
in  the  dog  (those  in  which  it  may  be  fairly  assumed  that  the  body  was 
neither  giving  up  stored  sugar  nor  storing  sugar,  storing  nitrogen  nor 
giving  up  stored  nitrogen,  where  the  experiments  were  prolonged  and 
controlled  and  where  preformed  carbohydrate  of  all  kinds  was  excluded) 
it  is  certain  that  the  glucose :  nitrogen  ratio  cannot  be  used  as  a  measure- 
ment of  the  formation  of  glucose  from  protein.  But  on  the  assump- 
tion that  diet  for  diet  this  is  a  fixed  faculty,  a  constant,  the  glucose : 
nitrogen  ratio  can  be  used  as  an  approximate  indication  of  the  loss 
or  retention  of  the  power  of  burning  glucose.  As  will  be  later  pointed 
out,  this  conclusion  is  supported  by  the  study  of  the  respiration  quotient. 
If  one  sweeping  assumption  be  made,  it  is  possible  on  the  basis  of 
the  experimental  data  to  regard  the  glucose-nitrogen  ratio  as  repre- 
senting the  ratio  of  formation  of  glucose  from  protein.  This  assump- 
tion is  that  amino-acids  build  sugar  only  via  lactic  acid,  and  the  avail- 
ability of  amino-acids  depends  upon  their  convertibility  into  lactic 
acid.  The  earlier  physiological  ratio  of  4.4  :  1  is  unquestionably 
too  high,  since  determined  early  in  the  tests.  When  fully  intoxicated 
with  phloridzin,  the  dog  burns  very  little  sugar,  as  may  be  shown  in 
experiments  by  direct  administration.     In  such  a  dog,  the  ratio  is 


320  METABOLISM 

usually  about  3.7  :  1.  On  the  basis  of  the  stated  assumption,  only 
one  molecule  of  lactic  acid  would  be  formed  from  each  molecule  of 
aspartic  and  glutamic  acids  and  from  leucin  and  lysin;  the  remainder 
of  the  carbons  would  be  burned.  If  now  we  calculate  the  amount  of 
lactic  acid  that  could  be  derived  from  a  protein  on  the  basis  of  this 
assumption,  we  obtain  values  that  lie  close  to  the  ratio  observed  in 
the  nitrogen  and  glucose  outputs  of  the  phloridzinized  dog.  The  amino- 
acids  in  casein  as  estimated  by  the  ester  method  make  up  only  about 
50  per  cent,  of  the  original  weight;  there  is  great  loss  in  the  procedures. 
Let  it  be  assumed  that  the  figures  at  hand  represent  the  relative  values 
and  these  we  will  double  to  secure  the  total.  When  now  these  different 
values  for  the  several  amino-acids  are  calculated  into  terms  of  lactic 
acid  and  this  then  into  glucose,  we  obtain  for  the  gram  of  casein  the 
figure  0.56  gram  of  glucose,  corresponding  to  the  ratio  3.5  :  1 — a  very 
close  approximation.  The  aromatic  amino-acids,  including  histidin, 
must  be  included  in  the  calculation.  The  assumption  is  rather  hazard- 
ous; but  the  concordance  is  certainly  striking. 

When  we  come  to  the  analyses  of  cases  of  clinical  diabetes,  we  find 
no  such  simple,  or  relatively  simple,  state  of  affairs.  This  must  be 
due,  in  large  part  or  even  entirely,  to  the  fact  that  it  is  not  possible 
to  make  the  determinations  of  the  glucose :  nitrogen  ratio  under  such 
conditions  of  control  as  are  possible  in  the  dog.  We  cannot  be  sure 
that  the  patient  is  not  eliminating  glucose  from  stored  carbohydrate, 
or  even  that  he  is  not  at  the  time  storing  glycogen.  We  cannot  be 
sure,  except  under  the  conditions  of  a  metabolic  balance  experiment, 
that  the  patient  is  not  retaining  nitrogen  or  losing  nitrogen,  or  catab- 
olizing  his  own  protein^  We  are  not  able  to  so  govern  the  diet  as  to  be 
certain  that  preformed  carbohydrate  is  excluded;  it  is  not  possible  to 
feed  a  human  diabetic  on  casein  or  codfish  flesh  for  a  period  of  days'. 
The  results  would  be  less  uncertain  if  we  were  able  to  make  the  deter- 
minations of  the  ratio  while  on  a  protein-fat  regimen  after  said  constant 
regimen  had  been  previously  persisted  in  for  a  week,  so  that  the  influ- 
ence of  previously  ingested  carbohydrate  could  be  eliminated;  but  it 
is  rarely  possible  to  so  diet  a  diabetic.  Under  all  these  circumstances 
it  ought  to  be  foreseen  that  the  glucose :  nitrogen  ratios  obtained  in 
the  study  of  clinical  diabetes  must  be  exposed  to  wide  variations  that 
ought  not  to  be  ascribed  to  the  disease  or  made  the  basis  for  inference. 

It  has  been  often  assumed  as  proper  that  a  limited  known  amount 
of  carbohydrate  may  be  added  to  the  diet  of  a  diabetic  when  the  ratio 
is  being  determined,  this  amount  to  be  subtracted  from  the  sugar  of 
the  urine  before  the  ratio  is  calculated,  on  the  obvious  assumption 
that  all  the  added  sugar  is  eliminated.  This  practice  cannot  be  coun- 
tenanced, as  it  adds  a  second  unknown  whereby  the  certainty  of  the 
ratio  determined  is  still  further  reduced.  If  the  respiratory  quotient 
were  shown  to  be  unchanged  by  the  addition  of  the  sugar,  and  this  were 
known  to  be  recovered  completely,  as  compared  with  a  period  without 
it,  the  procedure  might  be  permitted;  but  then  it  would  have  no  purpose, 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES 


321 


since  the  desired  ratio  would  have  been  obtained  in  the  fore-sugar 
period. 

The  glucose :  nitrogen  ratios  observed  in  clinical  diabetes  run  from 
1:1,  seen  in  mild  cases,  up  to  12  or  even  14  :  1.  The  ratio  is  usually 
in  direct  relation  to  the  severity  of  the  disease,  though  to  this  there 
are  striking  exceptions.  It  will  be  best,  in  the  discussion  of  these 
ratios,  to  make  of  them  three  subgroups:  Those  running  from  1  to 
5:1;  from  5  to  8  :  1;  and  those  ranging  above  8:1.  The  majority 
of  cases  of  diabetes  present  ratios  running  below  5:1.  There  are  very 
few  cases  as  low  as  1  :  1,  though  as  stated  there  are  typical  cases  of 
diabetes  that  have  no  glucosuria  on  a  protein-fat  diet.  Ratios  of  2 
to  3  :  1  may  perhaps  be  said  to  be  the  most  common,  and  one  of  the 
best  students  of  diabetes  has  termed  the  ratio  3.7  :  1,  when  deter- 
mined under  the  conditions  of  a  protein-fat  diet,  as  the  "fatal  ratio," 
higher  ratios  being,  of  course,  understood  to  be  equally  fatal. 

Let  us  place  these  ratios  and  their  meanings  in  concrete  terms  in  a 
table.  Let  it  be  assumed  that  the  subjects  are  in  nitrogen  balance, 
on  a  diet  of  fat  200  grams  and  protein  150  grams  a  day,  corresponding 
to  125  grams  glucose.  The  protein  of  the  diet  may  be  set  in  round 
figures  25  grams  per  day.  Under  these  circumstances,  for  the  following 
series  of  ratios,  we  have  the  following  values : 


Ratio 

Nitrogen 

Glucose  in  urine 

Glucose  burned  or  stored 

1  :  1 

25  grams 

25 

grams 

100  grams 

1.5  :  1 

25      " 

37 

tt 

87 

t 

2  :  1 

25      " 

50 

(C 

75 

< 

2.5  :  1 

25      " 

62 

u 

63 

• 

3  :  1 

25      " 

75 

u 

50 

' 

3.5  :  1 

25      " 

87 

a 

38 

1 

4  :1 

25      " 

100 

a 

25 

' 

4.5  :  1 

25      " 

112 

(4 

13 

' 

5  :  1 

25      " 

125 

(i 

0      " 

Glucose  derived  in  body 

outside  of  diet 

6  :  1 

25  grams 

150 

grams 

25  grams 

7  :  1 

25      " 

175 

ti 

50      " 

8  :  1 

25      " 

200 

u 

75      " 

9  :  1 

25  grams 

225 

grams 

100  grams 

10  :  1 

25      " 

250 

it 

125      " 

11  :  1 

25      " 

275 

u 

150      " 

12  :  1 

25      " 

300 

(( 

175      " 

13  :  1 

25      " 

325 

" 

200      ' 

1 

There  is  no  question  that,  as  a  rule,  the  severity  of  the  disease  runs 
parallel  to  the  inability  to  burn  glucose  and  to  the  height  of  the  glucose : 
nitrogen  ratio.  Assuming  that  on  the  average  these  cases  of  diabetes 
are  not  storing  large  amounts  of  glycogen  or  losing  large  amounts  of 
glycogen  previously  stored,  that  they  are  in  nitrogen  balance  and  that 
the  diet  prescribed  is  the  diet  actually  taken,  it  might  be  fairly  concluded 
that  when  below  5  :  1  the  ratio  is  a  general  index  of  the  power  of  the 

2i 


322  METABOLISM 

body  to  burn  sugar;  that  the  amounts  of  sugar  stated  in  the  table  (on 
the  basis  of  the  physiological  ratio  of  5  :  1)  to  be  derivable  from  the 
protein  in  the  diet  are  so  derived;  and  that  the  amounts  in  the  urine 
represent  the  fraction  not  burned,  the  difference  the  fraction  burned. 
If  we  could  be  certain  of  all  these  factors,  the  glucose-nitrogen  ratio 
would  be  a  very  useful  index  of  the  state  of  the  chief  defect  of  the 
diabetic,  the  power  of  burning  sugar. 

Many  cases,  however,  present  much  higher  ratios.  There  is  in  the 
table  a  group  including  6,  7  and  8:1,  that  are  grouped  by  themselves. 
Though  these  are  above  the  ratio  stated  as  regarded  as  the  normal 
physiological  ratio  (5:1)  they  are  still  within  the  ratio  that  would 
be  possible  if  all  the  carbon  of  the  molecule  of  protein  were  regarded  as 
converted  into  protein.  By  some  students  of  diabetes  it  is  held  that 
the  diabetic  organism  displays  the  pathological  faculty  of  converting 
into  glucose  the  full  carbon  content  of  the  molecule  of  protein,  this 
being  regarded  as  a  facultative  defect  of  the  disease.  We  shall  later 
refer  to  the  facultative  hypothesis  in  another  connection.  If  the  highest 
ratios  fell  within  8  :  1,  it  might  be  of  some  purpose  to  invoke  such  a 
hypothesis;  but  so  long  as  many  cases  present  ratios  greatly  in  excess 
of  this  for  which  explanations  must  be  found  outside  of  the  protein 
molecule,  there  is  no  purpose  in  this  hypothesis  for  the  middle  group 
of  cases.  The  extra  amount  of  sugar  involved  in  these  cases  is  not  large 
and  may  be  reasonably  accounted  for  by  reference  to  the  storage 
capacities  of  the  diabetic  body,  or  to  inexact  control  of  the  experiment. 

Now  a  few  cases  exhibit  decidedly  higher  ratios,  running  up  to  12  :  1. 
How  are  these  to  be  interpreted?  Here  the  excesses  of  sugar  are  large. 
Assuming  that  the  diet  has  been  controlled,  is  it  possible  to  derive 
these  in  any  way  from  the  stored  carbohydrates  of  the  body  or  from 
protein?  Or  are  we  to  assume  this  sugar  to  have  been  derived 
from  fat?  We  face  here  again  the  situation  that  confronted  us  when 
the  question  of  the  origin  of  glucose  from  protein  was  up  for  determina- 
tion. It  was  there  necessary  to  so  set  the  experiment  as  to  recover 
such  amounts  of  glucose  as  to  make  its  derivation  from  the  stored 
carbohydrates  of  the  body  quantitatively  impossible.  Here  it  is  neces- 
sary to  so  set  the  experiment  as  to  recover  such  amounts  of  glucose 
as  to  make  its  derivation  from  the  stored  carbohydrate  of  the  body 
and  from  the  protein  catabolism  quantitatively  impossible.  The  experi- 
ment has  been  so  carried  out  as  to  make  it  absolutely  certain  that 
the  body  produces  glucose  in  excess  of  all  possible  derivation  from 
carbohydrate;  and  it  has  been  possible  to  prove,  quite  positively,  its 
origin  from  protein  under  the  circumstances.  Has  it  been  possible  to 
recover  such  large  amounts  of  glucose  in  cases  of  diabetes  as  to  make 
the  carbohydrates  and  protein  both  unequal  to  its  origination,  leaving 
only  the  fat  to  serve  as  the  source  of  the  glucose?  This  question,  the 
origin  of  glucose  from  fat,  is  today  the  burning  question  in  diabetes. 

The  question  of  the  formation  of  sugar  from  fat  as  a  physiological 
process  will  be  discussed  in  another  chapter.     It  will  be  sufficient  to 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         323 

state  here  that  it  has  not  yet  been  proved  or  disproved.  If  sugar  were 
formed  from  fat  normally,  we  would  reasonably  infer  that  the  process 
holds  in  diabetes.  If  the  formation  of  sugar  from  fat  could  be  proved 
in  the  diabetic,  that  would  furnish  strong  grounds  for  the  inference 
that  such  a  process  occurs  in  health.  It  is  a  safe  rule,  when  applied  to 
the  main  streams  of  metabolism,  that  chemical  processes  are  fixed 
and  not  facultative.  And  while  a  normal  chemical  reaction  may  be 
lost  in  disease,  a  new  chemical  reaction  of  so  fundamental  a  character 
as  the  formation  of  sugar  from  fat  (or  from  protein)  is  hardly  to  be 
gained  in  disease.  It  may  be  possible,  in  a  disease,  to  uncover  a 
reaction  or  process  that  in  health  is  not  available  to  experiment.  If, 
therefore,  it  should  be  proved  in  diabetes  that  fat  is  converted  into 
sugar,  this  would  have  a  fundamental  bearing  upon  our  physiological 
conceptions. 

The  sugar  found  in  the  urine  in  the  cases  of  diabetes  with  high  ratios 
may  have  come  from  several  sources.  These  must  be  known  and  con- 
trolled in  any  attempt  to  decide  the  derivation  of  the  stated  sugar. 
It  may,  in  the  first  place,  have  come  from  preformed  carbohydrates 
of  the  diet.  We  insist  that  the  diet  of  the  diabetic  must  consist,  during 
the  period  of  the  test,  of  fat  and  protein.  This  standard  at  once  rules 
out  a  large  number  of  reported  cases.  More  than  this,  to  be  rigid,  the 
test  ought  to  have  been  preceded  by  a  number  of  days  of  the  fat-protein 
regimen,  and  the  test  should  run  over  not  one  but  several  days.  This 
would  eliminate  many  more  of  the  reported  cases  with  high  ratios. 

Could  the  amounts  of  sugar  involved  be  derived  from  tissue  glycogen? 
The  human  body,  when  rich  in  glycogen,  may  contain  as  much  as  two 
kilos  of  glycogen,  corresponding  to  two  and  a  half  kilos  of  glucose.  The 
diabetic  is  always  poor  in  glycogen,  and  it  may  be  assumed  that  no 
diabetic  in  the  active  stage  of  the  disease  has  a  kilo  of  glycogen  in  the 
body.  Unlike  the  depancreatized  dog,  who  travels  steadily  the  down- 
ward course,  human  diabetics  have  their  ups  as  well  as  downs,  periods 
in  which  glycogen  is  stored  being  followed  by  periods  in  which  the 
carbohydrate  is  swept  out  of  the  tissues.  It  is  clear  that  such  a  sweeping- 
out  of  the  glycogen,  in  the  form  of  sugar,  could  explain  a  high  glucose: 
nitrogen  ratio  for  a  number  of  days,  possibly  for  a  week.  By  this  fact 
others  of  the  reported  cases  of  high  ratios  are  made  uncertain  in  their 
meaning.  Conversely,  if  the  ratio  were  determined  in  a  period  of  storage, 
a  very  low  ratio  would  be  found,  fictitious  again  if  applied  to  the  factor 
of  the  combustion  of  sugar.  Theoretically,  the  determination  of  the 
respiratory  quotient  ought  to  place  us  in  the  position  of  deciding  whether 
the  body  is  burning  or  storing  the  retained  carbohydrate;  but  the 
practical  clinical  use  of  this  quotient  has  not  yet  been  placed  on  a  solid 
experimental  basis. 

In  the  opinion  of  the  writer,  the  amount  of  glucose  that  can  be 
calculated  as  derivable  from  the  glycerol  of  the  fat  undergoing  com- 
bustion ought  in  all  cases  to  be  subtracted  from  the  figure  for  glucosuria. 
This  would  rule  out  some  of  the  reported  cases. 


324  METABOLISM 

It  should  be  known  in  all  cases  that  there  is  no  nitrogen  retention. 
This  has  been  neglected  in  many  cases,  which  are  to  be  excluded. 
The  accurate  methods  of  the  metabolic  experiment  are  nowhere  more 
in  place  than  in  the  study  of  diabetes,  in  which  periods  of  nitrogen 
retention,  on  a  heavy  protein  input,  are  of  frequent  occurrence.  A 
slight  retention  of  nitrogen  would  result  in  a  marked  increase  in  the 
ratio. 

When  now  we  eliminate  from  the  literature  the  cases  of  high  glucose: 
nitrogen  ratios  in  which  the  necessary  controls  have  not  been  done, 
are  there  any  instances  left  in  which  the  sugar  recovered  from  the 
urine  was  in  such  amount  as  to  exclude  all  other  sources  of  derivation 
outside  of  fat?  The  question  must  be  answered  in  the  negative.  The 
writer  has  theoretical  preconceptions  in  favor  of  the  formation  of 
sugar  from  fat.  But  it  is  certain  that  the  proof  has  not  been  accom- 
plished in  the  study  of  diabetes.  The  figures  do  not  raise  a  reasonable 
presumption  in  favor  of  the  origin  of  glucose  from  fat.  What  the  data 
really  do  is  to  enable  us  to  state  the  question  concretely,  they  teach  us 
how  the  investigations  must  be  done  and  controlled.  The  decision 
must  be  left  to  future  measurements  in  which  the  shoals  of  past  mis- 
fortunes will  be  avoided. 

Upon  the  other  hand,  we  must  realize  that  the  arguments  that  are 
commonly  advanced  against  the  hypothesis  that  sugar  is  derived  from 
fat  in  the  diabetic  are  not  valid.  When  fat  is  given  to  a  diabetic  in 
excess,  the  glucosuria  is  not  increased;  in  a  word,  there  is  no  parallelism 
between  the  fat  ingestion  and  the  sugar  output,  as  there  is  so  often 
between  the  protein  input  and  the  glucosuria.  But  the  objection  is 
based  upon  a  misconception.  The  catabolism  of  protein  is  largely 
exogenous, t  it  is  a  function  of  the  input;  the  combustion  of  fat  and 
sugar  is  not  exogenous,  not  a  function  of  the  input,  but  solely  of  the 
body  needs.  One  cannot  stimulate  the  combustion  of  sugar  by  giving 
sugar,  or  of  fat  by  giving  fat;  the  excess  is  stored  for  future  use.  Since 
utilization  of  fat,  as  well  as  of  sugar,  is  not  dependent  upon  the  input, 
there  would  be  no  reason  to  expect  the  glucosuria  of  the  diabetic  to  be 
influenced  by  the  ingestion  of  fat,  even  were  sugar  derived  from  fat. 

The  fact  that  refrigeration  and  work  do  not  result  in  increase  in  the 
glucosuria  in  diabetes  and  in  phloridzin  intoxication,  though  they 
increase  the  fat  catabolism,  has  also  been  urged  as  an  argument  against 
the  origin  of  sugar  from  fat.  A  like  error  in  reasoning  lies  here  con- 
cealed. Work  does  not  increase  the  acetone  bodies  in  the  urine  of  the 
diabetic;  but  will  anyone  now  contend  that  these  are  not  derived  from 
fat?  Even  though  sugar  be  formed  from  fat — as  the  acetone  bodies 
certainly  are — it  would  not  necessarily  follow  that  sugar  and  the  acetone 
bodies  would  be  increased  when  the  combustion  of  fat  is  increased  by 
work. 

Upon  the  part  of  those  who  incline  to  regard  the  ratio  of  glucose 
to  nitrogen  as  an  index  of  the  capacity  or  act  of  formation  of  glucose 
from  protein,  an  explanation  of  the  higher  ratios  has  been  suggested 


THE  CARBOHYDRATE  METABOLISM  IN  DIABETES         325 

as  a  facultative  process,  i.  e.,  the  diabetic  forms  more  sugar  from  the 
unit  of  protein  than  does  the  normal.  This  explanation  is  too  lame  to 
travel  far.  There  is,  however,  a  school  of  physiologists  who  are  con- 
vinced that  the  formation  of  glucose  from  protein  in  toto  is  a  patho- 
logical process  peculiar  to  diabetes.  In  this  sense,  the  diabetic  would 
suffer  from  a  primary  overproduction  of  sugar.  According  to  this 
view,  the  body  normally  burns  directly  the  carbon  moiety  of  the  protein 
molecule;  in  the  diabetic  this  is,  so  to  speak,  side-tracked  to  glucose, 
which  being  incombustible  is  eliminated.  This  explanation  has  no 
proper  direct  foundation  and  is  opposed — entirely  apart  from  work 
on  diabetes — by  three  sets  of  facts  with  which  it  cannot  be  well  recon- 
ciled. The  normal  blood  contains  a  fore  stage  of  glucose,  which  in 
the  normal  liver  is  converted  into  glucose;  this  fore  stage  we  may 
reasonably  regard  as  amino-acid.  The  perfusion  of  the  normal  liver 
with  certain  amino-acids  results  in  the  formation  of  glucose.  And 
finally,  the  formation  of  glucose  from  protein  in  the  dog  with  phloridzin 
intoxication — which  is  certainly  not  diabetes — speaks  directly  against 
the  hypothesis.  The  mass  relations  speak  strongly  against  such  a 
view;  in  diabetes  we  have  hyperglucemia,  in  the  phloridzin  intoxica- 
tion we  have  hypoglucemia — yet  in  each  case  we  are  supposed  to  have 
a  pathological  facultative  formation  of  glucose  from  protein.  The 
hypothesis  is  too  far-fetched.  That  the  acts  of  digestion  have  nothing 
to  do  with  the  process  is  shown  by  the  fact  that  when  the  products 
of  a  predigestion  of  protein — amino-acids — are  given  to  the  dog  with 
phloridzin  intoxication,  the  formation  of  sugar  occurs  just  the  same. 
It  has  been  common  practice  in  the  treatment  of  diabetes  to  watch 
the  sugar  elimination  when  on  carbohydrate-free  diet,  and  mark  its 
concordance  with  the  protein  of  the  diet.  While  very  instructive  in 
many  cases,  it  was  early  known  that  striking  exceptions  occur.  The 
use  of  the  glucose :  nitrogen  ratio,  when  determined  under  conditions 
of  control,  is  without  question  of  much  greater  reliability,  and  should 
form  a  part  of  the  study  of  every  case  of  diabetes.  The  influence  of 
different  proteins  upon  the  formation  of  sugar  in  the  case  may  also 
be  studied  in  this  manner.  While  studies  on  the  adaptability  of  different 
proteins  to  the  formation  of  glucose  are  physiologically  very  difficult, 
the  practical  application  in  diabetes  of  such  proteins  as  yield  the  least 
sugar  is  made  possible  by  the  use  of  the  glucose-nitrogen  ratio.  Plant 
proteins  seem  to  yield  less  glucose  per  unit  than  animal  proteins;  and 
egg  albumin  often  yields  less  sugar  than  muscle  or  casein.  Such  studies 
must  be  carried  out  in  extenso  with  diabetics,  since  there  are  other 
factors  of  importance  that  can  only  be  fixed  by  thorough  study.  The 
time  of  digestion  is  undoubtedly  of  importance;  the  slower  the  pro- 
cesses of  digestion  and  assimilation  required  by  a  certain  protein,  the 
less  sugar — other  things  being  equal — the  body  will  form  from  it, 
since  more  time  will  be  afforded  the  powers  of  glycogenesis  and  of 
combustion  to  dispose  of  the  resulting  sugar.  The  simple  result  of 
less  sugar  to  the  unit  of  protein  does  not,  therefore,  mean  that  the 


326  METABOLISM 

protein  contains  intrinsically  less  sugar-forming  amino-acids;  it  may 
mean  simply  that  the  body  has  more  time  to  handle  the  products  of 
digestion — quite  in  the  same  sense  that  in  the  normal  individual  sugar 
in  quantity  can  always  produce  glucosuria  while  starch  can  do  so  in 
no  quantity. 

When  the  diabetic  loses  in  part  or  entirely  the  sugar  formed  from 
protein,  the  body  loses  by  that  much  the  heat  value  of  the  protein. 
After  subtracting  from  the  caloric  value  of  protein  the  caloric  value 
of  the  urinary  products  of  the  protein  catabolism,  the  heat  value  of 
protein  in  the  body  is  about  4  Calories  per  gram  protein.  Using  the 
physiological  ratio  of  5  grams  glucose  formed  from  protein  to  1  gram 
nitrogen,  1  gram  of  protein  would  yield  about  0.8  gram  sugar,  of  a 
heat  value  of  3  Calories;  if  all  this  sugar  were  lost  in  the  urine,  the 
protein  in  such  a  body  would  have  only  the  heat  value  of  1  Cal.  per 
gram.  This,  of  course,  represents  an  extreme  case.  But  instances 
are  common  in  which  at  least  half  the  sugar  is  lost,  so  that  the  caloric 
value  of  protein  becomes  reduced  to  2  —  2.4  Cal.  per  gram.  The  diabetic 
body  is  quite  in  the  situation  of  a  boiler,  built  with  a  wide  grate  for  the 
burning  of  large-size  coal,  being  fired  with  very  fine  coal,  much  of  which 
falls  unburned  into  the  ash-box.  The  catabolism  of  protein  is  under 
all  circumstances  attended  by  a  heat  loss  through  the  operation  of 
the  factor  of  the  specific  dynamic  action  of  protein.  This  heat  is  lost 
in  the  body  and  is  not  available  for  tissue  uses,  i.  e.,  not  convertible 
except  for  chemical  regulation  of  body  temperature  and  for  work. 
This  heat  is,  however,  not  a  total  loss  in  diabetes,  as  under  the  condi- 
tions of  the  total  metabolism  it  warms  the  body  and  possibly  permits 
the  combustion  of  fat  to  be  reduced  by  that  amount.  At  least  this 
is  the  interpretation  to  be  placed  upon  some  recent  estimations  of  the 
heat  production  in  diabetes;  it  seems  that  the  heat  production  due  to 
the  specific  dynamic  action  of  protein  is  not  in  diabetes  the  total  loss 
in  the  resting  state  that  it  is  in  the  normal  metabolism.  The  conver- 
sion of  protein  into  sugar  is,  as  a  chemical  reaction,  attended  with  a 
loss  of  heat  to  the  body,  it  is  an  endothermic  reaction.  If  all  the  carbon 
of  the  molecule  of  protein  were  converted  into  sugar,  this  would  yield 
about  1.4  grams  of  a  heat  value  of  5.1  Calories,  while  the  molecule  of 
protein  from  which  it  wae  formed  has  in  the  body  the  value  of  only 
4.4  Calories  at  the  best.  This  is  an  argument  against  the  conversion 
of  all  the  carbon  of  the  molecule  of  protein  into  glucose,  so  long  at 
least  as  one  inclines  to  the  view  that  the  chemical  processes  of  the 
body  proceed  along  the  simplest  lines. 

The  Formation  of  Sugar  from  Fat. — A  brief  resume  will  suffice  here. 
There  are  today  no  adequate  grounds  for  stating  or  rejecting  the 
hypothesis  of  the  origin  of  sugar  from  fat,  attractive  as  it  is  on  bio- 
logical and  chemical  grounds.  The  failures  of  attempts  to  increase 
glucosuria  in  the  diabetic  by  massive  ingestions  of  fat  prove  nothing, 
since  the  combustion  of  fat  is  not  a  function  of  the  input.  Whether 
lying  in  the  fatty  depots  or  regularly  ingested  in  the  diet,  the  body 


THE  COMBUSTION  OF  FAT  IN  DIABETES  327 

utilizes  of  fat  only  what  is  needed,  not  what  is  presented.  This  state- 
ment is  supported  by  the  observation  that  the  respiratory  quotient 
is  not  influenced  by  the  added  administration  of  fat  to  a  normal  diet. 
It  is  doubtful  if  the  question  can  ever  be  settled  except  by  quantita- 
tive experiment — the  recovery  in  the  urine  of  the  diabetic  of  more 
sugar  than  could  have  been  derived  outside  of  fat.  The  older  figures 
for  the  occurrence  of  the  acetone  bodies  offered  a  suggestive  hint  of 
the  origin  of  sugar  from  fat.  If  a  diabetic  were  to  eliminate  200  or  300 
grams  of  acetone  bodies  daily,  in  terms  of  beta-oxy-butyric  acid,  and 
each  molecule  of  the  acid  were  to  represent  one  molecule  of  higher 
fatty  acid,  it  would  follow  that  the  body  under  those  circumstances 
was  catabolizing  600  to  800  grams  of  fat  per  day — something  contra- 
dicted by  the  known  figures  for  the  heat  production.  This  discrepancy 
could  have  been  explained  by  the  conversion  of  a  portion  of  the  fatty 
acid  into  sugar.  The  newer  figures  for  the  amounts  of  acetone  bodies 
are  far  lower  than  those  previously  stated;  amounts  of  over  100  grams 
per  day  are  not  nowadays  reported,  and  50  grams  per  day  is  a  high 
output.  With  these  figures,  the  discrepancy  between  the  heat  pro- 
duction of  the  body  and  the  amount  of  fat  catabolized  (judged  by  the 
elimination  of  the  acetone  bodies)  is  not  striking,  even  in  the  cases 
of  highest  acidosis.  The  point,  however,  deserves  concrete  investiga- 
tion. Let  an  illustration  be  cited.  If  one  molecule  of  beta-oxy-butyric 
acid  be  derived  from  one  molecule  of  higher  fatty  acid,  then  to  form 
100  grams  of  beta-oxy-butyric  acid,  at  least  280  to  300  grams  of  fat 
must  have  been  catabolized.  This  fat  has  a  heat  value  of  about  2800 
Calories.  Subtracting  now  from  this  450  Calories,  the  heat  value  of 
the  beta-oxy-butyric  acid  lost,  we  have  2350  Calories,  to  which  must 
be  added  the  Calories  produced  in  the  inevitable  catabolism  of  protein, 
bringing  the  total  up  to  or  more  than  2600  Calories,  over  35  Calories 
per  kilo  per  day  for  a  body  of  70  kilos.  This  is  rather  a  high  figure, 
somewhat  in  excess  of  the  figures  noted  in  direct  estimations  in  diabetes. 
But  when  we  consider  that  the  elimination  of  100  grams  of  beta-oxy- 
butyric  acid  is  also  very  exceptional,  the  figures  do  not  more  than 
suggest  a  formation  of  sugar  from  protein,  nor  is  the  suggestion  striking. 


THE  COMBUSTION   OF   FAT  IN  DIABETES 

In  all  cases  of  established  diabetes  the  combustion  of  fat  is  quantita- 
tively excessive,  and  in  most  cases  qualitatively  defective,  just  as  in 
the  case  of  protein.  The  defects  in  the  metabolism  of  fat  may  not 
appear  early  in  the  course  of  the  disease,  but  eventually  they  may  be 
said  usually  to  dominate  the  situation.  We  saw  that  the  total  heat 
production  of  the  diabetic  per  kilo  per  minute  is  in  excess  of  the  normal. 
Glucose  can  be  burned  to  but  a  limited  extent;  the  loss  of  the  glucose 
derived  from  protein  reduces  greatly  the  heat  value  of  the  protein. 
With  more  heat  produced  and  with  sugar  and  protein  yielding  but  a 


:Y2S  METABOLISM 

fraction  of  the  normal  amount  of  heat,  the  burden  falls  upon  the  catab- 
olism  of  fat.  If  this  could  but  be  relied  upon  in  diabetes,  the  situation 
of  the  unfortunate  subject  would  be  hopeful.  But  the  catabolism  of 
fat  breaks  down,  so  that  not  one  support  of  the  tripod  remains  intact. 

Why  does  the  catabolism  of  fat  break  down  in  diabetes  ?  Is  it  simply 
a  result  of  overwork,  or  is  there  some  essential  defect  in  the  chemical 
mechanism?  It  cannot  be  simply  the  result  of  the  enforced  exaggera- 
tion of  function.  The  average  diabetic  is  fully  supplied  with  fuel 
when  given  100  to  150  grams  of  protein  and  200  to  250  grams  of  fat 
per  day.  Now  it  is  certain  that  a  normal  individual  could  take  such  a 
diet  indefinitely  with  no  other  untoward  result  than  a  slight  acetonuria. 
Many  barbarian  tribes  in  the  colder  regions  live  almost  entirely  on 
protein  and  fat.  Of  course,  the  situations  are  not  comparable;  for  the 
normal  individual  on  such  a  diet  utilizes  the  sugar  derived  from  the 
protein,  while  the  diabetic  does  not  in  large  part.  But  it  is  clear  that 
the  defect  in  the  catabolism  of  fat  in  diabetes  is  not  the  result  of  the 
excessively  fatty  diet  or  of  the  abnormal  dependence  placed  upon  the 
combustion  of  fat  as  the  chief  source  of  body  heat. 

This  brings  us  to  the  real  question.  Is  the  defect  in  the  combustion 
essential  and  primary  in  the  fat  metabolism,  a  direct  instance  of  metab- 
olic defect  as  is  the  loss  of  power  of  burning  sugar  ?  Or  is  it  a  secondary 
result,  like  the  exaggerated  catabolism  of  protein,  secondary  to  the 
defect  in  the  combustion  of  glucose?  This  is  the  second  crucial 
question  in  diabetes. 

In  the  normal  oxidation  of  fats,  these  are  first  hydrolyzed  to  the 
fatty  acid  and  glycerol,  the  latter  converted  into  sugar.  The  oxida- 
tion of  the  normal  fatty  acids  with  chains  of  carbons  in  even  numbers 
is  probably  effected  at  the  beta  atom  of  carbon,  and  results  in  the 
splitting  off  of  the  two  lower  carbons  of  the  fatty  acid,  the  alpha  and 
the  carboxyl  groups.  Thus  the  chain  is  made  two  carbons  shorter. 
This  process  is  then  repeated,  down  to  butyric  acid.  This  scheme 
holds  strictly  for  palmitic  and  stearic  acids,  and  for  the  purposes  of 
this  argument,  for  oleic  acid  also.  From  this  point  on  the  scheme  is 
uncertain,  as  will  be  detailed  in  another  section.  If  the  oxidation 
were  accomplished  by  attack  on  the  alpha  carbon,  we  would  have 
propionic  acid  formed  from  butyric  acid,  then  acetic  acid,  then  formic 
acid  and  complete  combustion.  If  the  oxidation  be  by  attack  on  the 
beta  carbon,  then  beta-oxy-butyric  acid  would  be  formed  from  butyric 
acid,  then  diacetic  acid.  Diacetic  acid  could  be  converted  into  acetic 
acid,  and  this  into  formic  acid  as  before.  There  is  no  question  but  that 
the  latter  is  the  course  in  diabetes,  any  question  pending  concerns  the 
normal  course.  Reserving  this  for  later  discussion,  in  diabetes  either 
the  body  forms  beta-oxy-butyric  acid  from  butyric  acid  as  an  abnormal 
reaction,  that  then  naturally  leads  to  diacetic  acid  and  acetone  (the 
acetone  group);  or  the  diabetic  has  lost  the  normal  power  of  burning, 
beta-oxy-butyric  acid  and  diacetic  acid.  Whatever  the  course,  the 
diabetic    metabolism    produces    and    contains    beta-oxy-butyric    and 


THE  COMBUSTION  OF  FAT  IN  DIABETES  329 

diacetic  acids  and  acetone  in  large  amounts,  and  this  is  the  basis  for 
the  acidosis  of  the  disease. 

Is  the  metabolic  defect  confined  to  the  lower  stages  of  the  process 
of  oxidation  of  the  fatty  acid,  to  and  below  the  butyric  acid?  In  the 
earlier  days,  when  the  methods  for  the  estimation  of  these  bodies 
were  imperfect,  such  large  amounts  of  acetone  bodies  were  supposed 
to  be  recovered  in  cases  of  diabetes  as  to  make  the  assumption  natural 
that  more  than  one  molecule  of  butyric  acid  might  be  produced  from 
higher  fatty  acid — unless  one  were  to  invoke  the  formation  of  sugar  from 
fat.  Nowadays  we  know  that  the  amount  of  the  acetone  bodies  formed 
in  diabetes  is  not  so  large  as  to  make  such  an  assumption  proper.  It  may, 
therefore,  be  regarded  as  certain  that  in  diabetes  but  one  molecule  of 
butyric  acid  is  formed  from  one  molecule  of  higher  saturated  fatty 
acid;  the  defect  in  the  combustion  of  fat  lies  below  the  stage  of  butyric 
acid.  The  exaggeration  of  the  fat  metabolism  is  made  evident  in  the 
excess  of  fat  to  be  found  in  the  blood,  liver,  and  muscles  in  diabetes, 
in  striking  contrast  to  the  paucity  of  glycogen  in  the  same  tissues. 

In  the  section  dealing  with  the  fat  metabolism  will  be  found  a  detailed 
discussion  of  the  question  of  the  derivation  of  the  acetone  bodies. 
While  there  is  evidence  that  these  might  be  derived,  in  small  amounts 
at  least,  from  glucose  and  protein,  it  is  certain  that  in  diabetes — and 
probably  under  all  other  conditions  where  the  clinical  complex  occurs 
— they  are  derived  from  fat.  The  quantitative  relations  alone  make 
this  conclusion  necessary.  Many  cases  of  diabetes  eliminate  amounts 
of  the  ketonic  bodies  that  could  not  possibly  have  been  derived  from 
glucose  or  protein.  One  case  has  been  reported  in  which  a  diabetic, 
ingesting  no  carbohydrate,  eliminated  97  grams  of  acetone  bodies  and 
40  grams  of  sugar,  with  nitrogen  in  the  urine  corresponding  to  a  protein 
catabolism  of  only  90  grams.  This  is,  of  course,  an  extreme  case. 
But  instances  are  common  in  which  the  acetone  bodies  could  not 
possibly  have  been  derived  from  the  glucose  and  protein,  but  must 
have  been  derived  from  fat.  In  the  diabetic  we  will,  therefore,  regard 
it  as  settled  that  the  ketonic  bodies,  the  acidosis,  are  of  fatty  origin. 

When  the  substances  concerned  are  administered  to  the  diabetic, 
we  obtain  interesting  results.  Butyric  acid  is  almost  quantitatively 
converted  into  beta-oxy-butyric  acid.  When  beta-oxy-butyric  acid 
is  administered,  it  is  not  oxidized  but  is  eliminated.  Propionic  acid 
and  acetic  acid  are  oxidized  as  in  the  normal.  Diacetic  acid  is  in  part 
oxidized,  in  part  eliminated,  in  part  converted  into  acetone.  Acetone 
is  not  oxidized  in  the  body,  normal  or  diabetic,  to  any  notable  extent. 
Whether  the  diabetic  organism  converts  diacetic  acid  into  acetone  to  a 
greater  relative  or  absolute  extent  than  does  the  normal  metabolism  is 
not  known.  The  normal  body  oxidizes  beta-oxy-butyric  acid  very  well, 
diacetic  acid  also. 

Elimination  of  Acetone  Bodies. — The  amounts  of  the  acetone  bodies 
that  are  eliminated  in  diabetes  are  subject  to  great  variations  in  total 
and  in  the  relative  proportions.    When  the  total  amount  of  the  acetone 


330  METABOLISM 

bodies  is  low,  acetone  may  be  the  only  member  present,  and  is  always 
the  predominating  one.  As  the  total  output  increases,  the  diacetic 
acid  and  the  beta-oxy-butyric  acid  become  more  and  more  prominent, 
especially  the  latter.  In  the  massive  eliminations,  the  beta-oxy-butyric 
acid  is  always  in  largest  amount,  the  diacetic  acid  and  acetone  in  small, 
or  even  nominal  amounts.  For  instance,  there  may  be  50  grams  of 
beta-oxy-butyric  acid,  10  grams  of  diacetic  acid,  and  5  grams  only  of 
acetone.  This  is  due  to  the  fact  that  the  capacity  of  the  diabetic  body 
for  the  distoxication  of  diacetic  acid  by  conversion  into  acetone  is 
limited;  and  the  capacity  of  the  diabetic  body  for  oxidation  of  the 
beta-oxy-butyric  acid  to  diacetic  acid  is  limited.  The  total  figures 
are  difficult  of  exact  estimation,  partly  because  some  of  the  acetone 
is  eliminated  in  the  expired  air  and  some  of  both  acids  in  the  perspira- 
tion, but  also  because  of  difficulties  in  the  analytical  methods.  The 
amount  of  acetone  in  the  expired  air  has  been  greatly  overestimated. 
It  is  also  important  to  know  that  the  breath  in  diabetic  coma  may 
present  a  fruit-like  odor  that  can  be  shown  not  to  be  due  to  acetone. 
A  total  ketonic  elimination  of  20  grams  per  day  is  common,  elimina- 
tions of  over  50  grams  are  uncommon,  up  to  100  grams  very  rare  and 
seen  only  in  diabetic  coma.  The  administration  of  alkali  often  seems 
to  result  in  a  sweeping  out  of  the  substances,  though  sometimes  this 
is  not  observed;  and  in  particular  it  is  on  the  two  acids  and  not  on  the 
acetone  that  the  effect  is  apparent.  In  other  words,  the  binding  of  the 
acids  with  external  alkali  has  no  effect  upon  the  powers  of  conversion 
into  acetone.  Occasionally  one  will  see  a  case  of  diabetes  with  little 
glucosuria,  a  low  protein  catabolism  and  a  total  elimination  of  30  to 
40  grams  of  acetone  bodies,  with  few  symptoms,  the  subject  remaining 
in  this  state  for  a  long  time. 

There  are  two  methods  of  distoxication  of  the  acids  (since  oxidation 
fails):  by  conversion  into  acetone  and  by  neutralization.  Neither  is 
perfect,  since  the  acetone  is  somewhat  toxic,  and  the  salts  of  beta-oxy- 
butyric  acid  are  also  toxic.  As  stated,  the  amount  that  can  be  converted 
into  acetone  is  limited.  The  function  of  neutralization  is  not  limited; 
the  amount  of  ammonia  that  is  to  be  derived  from  the  protein  catab- 
olism is,  in  mass,  always  sufficient  to  combine  with  all  the  acids  ever 
produced  in  diabetes.  The  difficulties  lie  in  the  affinity  constants  of  the 
different  cations,  and  in  the  strength  of  combination  of  the  fixed  cations 
in  the  tissues.  If  the  acids  were  but  eliminated  entirely  as  ammonia 
salts,  all  would  be  well.  But  as  they  circulate  they  abstract  from  the 
tissues  sodium,  potassium,  and  calcium  and  thus  disturb  the  equilib- 
rium of  the  cations  in  the  tissues.  Obviously  the  correct  therapeutic 
measure  is  not  to  administer  an  alkali  of  one  cation — as  sodium  bicar- 
bonate— but  a  mixture  of  sodium,  potassium,  and  calcium,  in  order 
that  all  these  may  be  present  in  abundance  in  the  tissues  and  the 
equilibrium  of  the  cations  in  the  central  nervous  system  thus  main- 
tained. To  simply  give  sodium  is  little  better  than  what  the  body 
does,  offer  only  ammonia.     This  proposition  is  based  upon  the  law 


THE  COMBUSTION  OF  FAT  IN  DIABETES  331 

of  mass  action,  and  has  the  support  of  much  experimental  work  in 
general  biology.  The  place  to  test  it  in  diabetes  is  not  in  the  attack 
of  coma — when  the  damage  is  done — but  in  the  daily  administration 
of  alkali,  to  such  an  extent  that  the  ammonia  of  the  urine  is  reduced 
to  normal.  A  case  is  on  record  in  which  a  diabetic  had  taken  sodium 
bicarbonate  daily  for  years.  Three  days  after  the  cessation  of  the  drug, 
an  attack  of  coma  occurred.  Obviously,  through  all  this  time  while 
sodium  was  being  given,  potassium  and  calcium  were  being  abstracted 
from  the  tissues,  since  no  amount  of  sodium  can  prevent  the  potassium 
and  calcium  from  participating  in  the  mass  reaction  of  neutralization. 
The  results  of  alkali  therapy  would  without  question  be  more  certain, 
if  all  the  cations  are  administered.  It  must  be  recalled  that  potassium 
and  calcium,  outside  of  the  blood  stream,  outweigh  sodium;  especially 
potassium,  which  in  some  organs  is  present  to  four  hundred  times  the 
amount  of  sodium. 

The  ammonia  of  the  urine  in  subjects  not  taking  alkali  stands  as 
a  general  index  of  the  amount  of  ketonic  acids.  The  ammonia  of  the 
normal,  rarely  over  0.5  gram  per  day,  is  often  exceeded;  the  output  may 
be  2  or  3  grams,  5  or  6  in  severe  cases,  up  to  10  or  12.  There  is  no  ques- 
tion that  a  high  figure  for  ammonia  is  a  danger  signal.  Each  gram 
of  ammonia  represents  about  6  grams  of  beta-oxy-butyric  acid.  And 
as  the  estimation  of  urinary  ammonia  is  comparatively  easy,  the 
estimation  of  the  ketonic  acids  may  be  conveniently  accomplished  in 
this  way.  The  action  of  administered  alkali  may  also  be  measured  in 
this  way.  When  fixed  alkali  is  given,  the  cation  will  not  replace  directly 
and  at  once  the  ammonia  in  molecular  relations.  If  we  administer 
1  gram  mol.  of  sodium  bicarbonate,  it  will  not  displace  1  gram  mol. 
of  ammonia  from  the  urine  (one  part  ammonia  to  six  parts  sodium 
bicarbonate) .  Usually  much  less  ammonia  will  be  driven  from  the  urine, 
though  in  some  cases,  after  a  few  days,  nearly  the  theoretical  amount 
may  be  displaced.  Sometimes  the  amount  of  ammonia  that  is  dis- 
placed is  very  low;  thus  the  daily  administration  of  20  grams  of  sodium 
bicarbonate  may  lower  the  urinary  ammonia  only  1  gram.  We  deal 
here  with  mass  relations  that  are  not  yet  definable.  Two  explanations 
suggest  themselves.  One  is  that  a  part  of  the  fixed  alkali  administered 
is  held  in  the  tissues  to  replace  cations  that  have  been  abstracted  by 
the  acidosis.  This  is  surely  true,  but  it  cannot  explain  the  gross  results. 
The  second  explanation  is  that  the  alkali  is  given  in  a  few  large  doses, 
often  with  the  meals.  It  is  quickly  absorbed,  for  a  short  time  the 
circulation  is  flooded,  it  is  eliminated  and  there  are  long  periods  in 
the  day  and  during  the  night  when  none  of  it  is  in  operation  and  the 
ammonia  alone  is  available.  If  the  fixed  alkali  were  to  be  administered 
often,  say  in  hourly  doses  during  the  day,  with  a  heavy  dose  on  retiring, 
a  better  action  might  be  anticipated.  Beyond  this,  it  must  be  expected 
that  some  ammonia  would  remain  simply  as  an  incident  of  circula- 
tion. To  drive  out  the  ammonia  from  urine — to  render  the  normal 
urine  ammonia-free — requires  not  less  than  90  grams  of  sodium  bicarbo- 


332  METABOLISM 

nate  per  day.  It  may  be  assumed  that  when  fixed  alkali  is  administered, 
it  will  be  localized  more  in  the  tissues  than  in  the  circulating  blood; 
that  is,  in  any  moment,  the  blood  would  have  a  lower  binding  power 
for  it  than  have  the  tissues.  It  may  be  taken  for  granted  that  the 
formation  of  the  ketonic  acids  occurs  in  the  liver,  where  occurs  also 
the  formation  of  ammonia;  the  combination  of  the  two  occurs  in  situ. 
A  part  of  the  blood  streaming  from  the  liver  would  go  from  the  heart 
directly  to  the  kidney,  and  from  this  we  would  expect  the  ammonium 
oxy-butyrate  to  be  eliminated.  The  larger  portions  would  go  to  the 
tissues,  there  to  meet  with  greater  amounts  of  the  alkali,  with  the 
result  of  a  binding  of  the  fixed  cation  with  the  acids,  the  ammonia 
being  set  free  to  return  to  the  liver  and  be  converted  into  urea.  And, 
lastly,  it  must  not  be  supposed  that  the  different  cations  would  act 
as  they  would  if  placed  with  the  fatty  acids  in  a  test-tube.  There 
are  especial  affinities  of  cations  for  tissue  components,  ion-protein 
combinations,  that  must  play  an  important  role. 

Tissues  combine  with  acids  as  well  as  with  cations.  It  is,  therefore, 
not  to  be  denied  that  the  beta-oxy-butyric  acid  might  be  in  combina- 
tion with  tissue  components,  and  these  might  be  difficult  of  prompt 
dislodgement.  There  is  no  evidence  that  the  salts  in  the  blood  are 
bound.  The  normal  neutral  reaction  of  the  blood  is  not  altered  in  the 
most  severe  cases,  though  naturally  its  CO2  content  is  reduced.  In 
the  coma  of  acidosis  an  acute  acapnia  occurs.  This  is  due  in  part  to 
the  presence  of  the  ketonic  acids  in  the  blood,  in  part  to  hyperpnea, 
the  disturbance  in  respirations  being  caused  by  the  acetone  in  the 
circulation. 

The  study  of  the  urine  in  untreated  cases  has  shown  wide  varia- 
tions in  the  salt  content  from  the  normal.  Calcium  and  magnesium 
have  been  found  in  marked  excess.  For  potassium  no  data  are  at 
hand.  It  has  been  usually  assumed  that  the  calcium  was  abstracted 
from  the  bones.  But  there  is  evidence  that  the  calcium  of  the  nervous 
system  is  in  a  state  of  more  labile  combination  than  in  bone;  and  the 
abstraction  of  a  small  amount  would  be  expected  to  lead  to  pronounced 
symptoms.  A  finding  that  is  very  suggestive  in  this  connection  is  that 
of  increase  in  the  endogenous  purin,  indicating  an  exaggerated  nucleic 
catabolism.  Since  it  has  never  been  possible  to  show  a  primary  abnor- 
mal catabolism  of  protein  in  diabetes,  it  is  to  be  inferred  that  we  have 
here  a  specific  nuclear  disturbance,  which  might  well  be  associated 
with  a  disturbance  in  the  equilibrium  of  the  cations  in  the  nucleus. 
It  has  been  stated  that  the  phosphoric  acid  of  the  urine  is  in  excess 
in  many  cases  of  diabetes;  this  could  be  derived  from  either  nuclear 
catabolism  or  from  the  bone.  Upon  these  statements  no  interpreta- 
tion may  be  placed  today,  since  observations  on  the  urinary  phosphoric 
acid,  without  knowledge  of  the  input  and  of  the  fecal  output,  have 
little  meaning  except  to  mislead. 

Apart  from  the  three  bodies  that  we  group  under  the  term  of  "  acetone 
bodies,"  the  urine  contains  volatile  acids,  and  these  are  usually  also 


THE  COMBUSTION  OF  FAT  IN  DIABETES  333 

increased  in  diabetes.  Whether  they  come  from  the  fat  catabolism 
or  whether  they  indicate  the  failure  of  the  body  to  oxidize  the  volatile 
acids  elsewhere  derived,  is  not  known.  Fatty  acids  above  acetic  acid 
increase  the  acidosis  in  diabetes;  and  it  is  possible  that  the  fatty  acids 
resorbed  from  the  intestine  (due  to  bacterial  action  on  carbohydrates) 
are  eliminated  in  part  as  ketonic  bodies;  in  part,  however,  unchanged. 

Butter,  on  account  largely  of  its  content  of  butyric  acid,  increases 
notably  the  output  of  the  acetone  bodies.  As  elsewhere  stated,  triolein 
yields  a  larger  amount  than  do  tripalmatin  and  tristearin.  Under 
these  conditions  butter  and  the  liquid  fats,  like  olive  and  cotton-seed 
oil,  are  not  so  adapted  to  the  diet  in  diabetes  as  the  fats  of  beef  and 
mutton  flesh.  But  the  attempt  to  induce  the  diabetic  to  consume 
daily,  for  any  length  of  time,  200  grams  of  beef  or  mutton  fat  is  likely 
to  arouse  a  revulsion  to  the  diet,  so  that  it  may  be  necessary  to  include 
butter  and  olive  oil,  even  though  they  yield  more  beta-oxy-butyric 
acid,  oleic  acid  yielding  three  molecules  of  butyric  acid. 

A  large  number  of  substances  act  antiketonically,  i.  e.,  depress  the 
formation  of  the  acetone  bodies.  All  substances  that  can  yield  glucose 
in  the  metabolism  do  so  act  as  a  rule.  Thus  starches,  sugars,  protein, 
glycerol,  pentoses,  and  lactic  acid  all  so  act.  Some  substances  act 
in  this  way  that  are  not  known  to  form  sugar  in  the  body;  thus  ethyl 
alcohol,  citric  acid  and  d-gluconic  acid  do  so.  The  sugars  and  sugar- 
bearing  substances  act  not  in  proportion  to  their  ingestion,  but  in 
proportion  to  their  combustion.  The  ingestion  of  fat  in  excess  of  the 
needs  of  the  body  does  not  have  any  effect  upon  the  acetone  bodies. 
The  ingestion  of  protein  is  usually  followed  by  a  reduction  in  the  acetone 
bodies,  the  increased  catabolism  of  protein  sparing  the  combustion 
of  fat.  The  ingestion  of  ethyl  alcohol,  while  it  reduces  the  acidosis, 
in  some  manner  seems  to  reduce  also  the  toleration  for  glucose. 

To  the  usual  findings  there  are  some  striking  exceptions,  (a)  Some 
diabetics  exhibit  a  good  toleration  for  sugar  up  to  100  grams  per  day, 
with  heavy  and  continuous  acidosis,  (b)  Some  diabetics  have  little 
or  no  toleration  for  glucose,  with  little  acidosis  over  such  long  periods 
of  time  as  reasonably  to  exclude  the  action  of  the  body  glycogen,  (c) 
In  some  cases  of  diabetes,  carbohydrates  display  little  or  no  anti- 
ketonic  action,  even  though  there  is  evidence  that  some  of  the  ingested 
sugar  is  burned,  (d)  Some  cases  of  diabetes  display  no  increase  in  the 
acetone  bodies  when  carbohydrates  are  cut  out  from  the  diet,  (e) 
In  some  cases  of  diabetes,  with  a  constant  output  of  nitrogen  and  of 
glucose,  the  output  of  acetone  bodies  may  fluctuate  up  and  down  in 
the  most  irregular  manner.  (/)  In  some  cases  of  diabetes,  improving 
under  diet  and  treatment,  the  acetone  bodies  persist  after  the  glucosuria 
has  disappeared,  (g)  In  some  cases,  exercise  does  not  have  the  usual 
reciprocal  influence  on  the  combustion  of  sugar  and  of  fat,  as  revealed 
in  the  acidosis. 

The  rule  is  that  acidosis  exists  in  inverse  relation  to  the  combustion 
of  glucose;  the  less  the  power  of  burning  glucose,  the  greater  the  acidosis. 


334  METABOLISM 

Or,  in  dynamic  words,  the  less  the  power  of  burning  glucose,  the  less 
the  power  of  burning  fat.  Since  according  to  our  present  conceptions, 
it  is  only  from  the  stage  of  butyric  acid  that  the  difficulty  lies,  we  may 
state  the  situation  more  concretely;  the  less  the  power  of  splitting 
glucose,  the  less  the  power  of  burning  butyric  acid.  How  are  we  to 
interpret  this  remarkable  relationship? 

The  current  interpretation  is  that  the  combustion  of  butyric  acid 
is  directly  related  to  the  combustion  of  glucose.  In  the  language  of 
one  of  the  German  writers,  "  Fat  is  burned  only  in  the  fire  of  carbo- 
hydrate." A  mechanical  illustration  will  make  this  hypothesis  more 
tangible.  Crude  oil  will  not  burn  directly.  When,  however,  it  is 
sprayed  with  a  jet  of  steam,  it  burns  well.  Here  it  is  a  question  probably 
of  physical  state  only.  In  the  case  of  the  combustion  of  fat,  we  are 
to  infer  that  at  some  stage  in  the  oxidation  of  butyric  acid  there  is  a 
fixed  relationship  to  some  stage  in  the  cleavage  of  glucose;  if  the  latter 
be  not  present,  the  former  is  not  accomplished.  In  many  instances, 
the  acidosis  seems  related  less  to  the  momentary  inability  to  burn 
ingested  sugar  than  to  the  depletion  of  the  glycogen  of  the  tissues; 
and  certainly  the  extreme  depletion  of  the  body  glycogen  places  the 
diabetic  in  danger  of  an  explosion  of  acidosis,  of  diabetic  coma. 

The  exceptions  to  this  rule  of  direct  relationship  are,  however,  so 
frequent  and  sometimes  so  glaring,  that  this  hypothesis  of  intercom- 
bustion  is  not  accepted  by  all.  The  facts  could  be  explained  by  the 
assumption  of  a  direct  enzymic  defect  in  the  combustion  of  butyric 
acid,  just  as  in  the  case  of  the  combustion  of  glucose.  Under  this 
interpretation  the  action  of  the  combustion  of  glucose  becomes  simply 
one  of  a  division  of  burden.  Anything  that  exaggerates  a  defective 
metabolism  makes  the  defect  more  apparent.  Anything  that  spares 
a  defective  metabolism  makes  the  defect  less  apparent.  When  no 
sugar  is  burned,  the  entire  burden  falls  upon  the  combustion  of  fat, 
and  the  defect  (the  acidosis)  becomes  exaggerated;  when  some  sugar 
is  burned,  the  combustion  of  fat  is  spared,  and  the  defect  (the  acidosis) 
becomes  less  apparent.  Obviously,  under  such  an  interpretation, 
other  factors  than  the  combustion  of  sugar  could  influence  the  com- 
bustion of  fat  and  modify  the  diabetic  defect  in  this  catabolism.  The 
numerous  exceptions  to  the  usual  rule  quoted  above,  are  not  out  of 
harmony  with  this  hypothesis.  In  particular,  one  other  behavior 
deserves  attention.  It  has  been  observed  in  severe  cases  of  diabetes 
that  the  ingestion  of  increased  amounts  of  protein,  instead  of  lowering 
the  acidosis,  may  increase  it.  And  it  seems  that  in  severe  diabetes, 
anything  that  increases  the  glucosuria,  the  introduction  into  the  body 
of  glucose  that  cannot  be  utilized,  tends  to  depress  the  combustion  of 
fat  and  to  increase  the  acidosis.  In  one  reported  instance,  an  attack 
of  diabetic  coma  followed  directly  the  introduction  of  carbohydrate 
into  the  diet.  This  is  easy  of  comprehension  if  we  assume  a  fermenta- 
tive defect  in  the  fat  catabolism.  Then  any  injury  would  naturally 
exaggerate  the  defect,  and  the  combustion  of  fat  would  be  injured  by 


THE  RESPIRATORY  QUOTIENT  IN  DIABETES  335 

the  hyperglucemia  just  as  the  combustion  of  glucose  is  injured  by  the 
hyperglucemia.  Harmonious  also  to  this  view  is  the  action  of  com- 
bustible substances  that  spare  fat  combustion  but  do  not  form  sugar. 
Thus  ethyl  alcohol,  simply  by  sharing  the  burden  of  heat  production, 
reduces  the  acidosis  without  in  the  least  aiding  the  combustion  of 
glucose  or  being  itself  converted  into  glucose.  Other  objections  to  the 
view  that  acidosis  occurs  in  diabetes  only  because  fat  cannot  be  burned 
except  in  the  fire  of  carbohydrate,  will  be  stated  in  the  discussion  of  the 
whole  subject  of  acidosis,  in  the  chapter  devoted  to  the  fat  metabolism. 
Associated  with  the  acidosis  of  diabetes  is  usually  found  an  exces- 
sive lipemia.  The  highest  figure  for  the  total  fat  content  of  the  blood, 
under  conditions  when  the  fat  catabolism  is  worked  to  the  normal 
maximum  (in  starvation  and  in  the  use  of  a  fat-protein  diet)  is  not  over 
1  per  cent.  In  severe  diabetes  we  may  find  six  to  ten  times  as  much, 
the  fat  coming  either  from  the  diet  or  from  the  fat  depots  of  the  body. 
Normally,  the  blood  can  handle  (i.  e.,  convert  into  the  soluble  state 
and  deposit  in  the  tissues)  more  fat  than  the  diabetic  blood  contains. 
In  some  way  in  diabetes  the  mechanism  of  the  solution  of  fat  in  the 
blood  serum  and  its  transportation  through  the  body  is  disarranged. 
The  blood  has  a  singular  capacity  for  the  solution  of  fat  at  neutral 
reaction,  the  component  factors  of  this  solubility  being  not  under- 
stood. We  may  assume  the  fat  in  solution  to  be  the  metabolic  state, 
i.  e.,  it  is  the  fat  in  solution  and  not  the  fat  in  suspension  that  is  utilized 
in  metabolism.  Now  in  the  normal  the  blood  carries  little  of  the  fat 
in  suspension,  it  is  promptly  carried  to  the  fat  depots  and  deposited. 
In  diabetes,  this  is  not  the  case;  the  blood  is  loaded  with  a  vast  excess 
of  fat  in  suspension,  which  we  do  not  believe  has  any  metabolic  func- 
tion, but  is  there  simply  as  dead  weight  because  it  has  failed  of  deposi- 
tion or  has  been  withdrawn  from  the  depots  in  excess  of  requirements. 
Not  only  is  the  fat  in  suspension  increased,  the  fat  in  solution  seems 
to  be  reduced.  It  is  possible  that  the  defective  lipogenesis  noted  in 
diabetes  is  associated,  in  part,  with  the  reduced  content  of  soluble  fat 
and  the  increased  content  of  suspended  fat  in  the  blood.  In  any  event, 
these  states  suggest  a  more  primary  defect  in  the  fat  catabolism  than 
simply  direct  dependence  upon  the  combustion  of  glucose.  When 
one  contemplates  the  metabolism  of  an  advanced  case  of  diabetes,  one 
must  realize  that  it  is  quite  the  same  as  in  the  case  of  the  one-horse 
shay. 

THE   RESPIRATORY   QUOTIENT   IN   DIABETES 

rpU  .     ,  ..     .  /Expired  C02  c.c.\  .  „ 

I  he   respiratory   quotient  1-^ = — t~^ )  is  a  matter   ot  great 

importance  in  diabetes,  because  it  affords  indications  as  to  the  type 
of  materials  undergoing  combustion.  Of  importance  in  research  it 
now  is;  of  great  clinical  interest  it  would  surely  be  if  it  could  be  readily 
determined.    The  quotient  for  the  combustion  of  sugar  is  1;  that  for 


336  METABOLISM 

the  combustion  of  fat  is  0.71 ;  that  for  the  combustion  of  protein  may 
be  set  at  0.8;  though  it  is  doubtless  different  in  different  proteins,  since 
the  carbon  content  of  proteins  vary  from  50  to  55  per  cent.,  and  the 
oxygen  content  from  18  to  24  per  cent.  Obviously,  if  the  simplest 
relations  were  assumed  to  hold  and  we  knew  the  protein  and  carbo- 
hydrate content  of  the  diet  of  a  diabetic,  by  a  comparison  of  his  respira- 
tory quotient  with  that  of  the  normal  subject  on  the  same  diet,  we 
could  determine  the  utilization,  or  rather  combustion,  of  the  carbo- 
hydrate. This  cannot  be  done  by  the  estimation  of  the  glucose  in 
the  urine,  because  we  cannot  separate  glucose  burned  from  glucose 
stored.  That  it  cannot  be  done  directly  with  the  use  of  the  glucose: 
nitrogen  ratio  has  been  already  stated.  In  a  similar  manner,  the 
determination  of  the  quotient  in  a  diabetic  subject  on  a  fat-protein 
diet  would,  by  comparison  with  the  quotient  of  a  normal  body  on 
the  same  diet,  indicate  to  what  an  extent  the  body  could  burn  the 
sugar  derived  from  protein.  It  is  clear,  however,  from  the  present, 
already  extensive  data,  that  these  simple  relations  do  not  hold.  And 
the  interpretations,  although  they  follow  approximately  the  lines 
indicated,  cannot  be  made  as  direct  as  we  would  wish.  There  are 
several  factors  that  tend  to  invalidate  the  direct  interpretation  of  the 
respiratory  quotient. 

(a)  The  quotient  for  the  combustion  of  fat  is  set  at  0.71.  This 
is  in  itself  a  rounded  sum,  since  the  quotient  must  be  a  little  higher 
for  triolein  than  for  tristearin  and  tripalmatin.  But  in  diabetes  a  new 
factor  enters.  In  the  figure  0.71  the  glycerol  is  regarded  as  burned; 
in  diabetes,  however,  this  glycerol  after  conversion  into  glucose  is 
only  partially  burned,  and  may  indeed  often  be  regarded  as  entirely 
eliminated.    This  would  reduce  the  quotient  to  possibly  0.69. 

(b)  The  quotient  for  protein  is  set  at  0.8.  This  is  under  the  condi- 
tion that  the  glucose  derived  from  it  is  burned.  But  in  diabetes  this 
is  the  case  only  in  part,  in  part  this  sugar  is  lost.  The  quotient  for 
the  combustion  of  protein  following  the  subtraction  of  the  amount  of 
sugar  represented  in  the  glucose :  nitrogen  ratio  of  5  :  1  would  be  as 
low  as  0.6.  Depending  upon  the  degree  of  retention  of  the  power  of 
burning  the  sugar  derived  from  protein,  this  quotient  would  vary  from 
0.6  to  0.8.  This  indicates  at  once  that  in  diabetes  we  may  expect 
sometimes  to  find  the  respiratory  quotient  below  0.7,  below  the  lowest 
figure  for  the  physiological  combustion  of  any  foodstuff. 

(c)  The  respiratory  quotient  may  be  influenced  by  the  diet  of  the 
day  previous.  Now  it  is  not  practicable  to  have  diabetics  fast  over  a 
whole  day,  so  as  to  reduce  this  disturbing  element.  It  will  usually 
be  found  necessary  to  determine  the  quotient  with  not  over  twenty- 
hour  fast.  If  it  could  be  assumed  that  the  diabetic  had  lost  entirely 
the  power  of  storing  glucose  as  glycogen  and  then  yielding  it  to  com- 
bustion during  the  fasting  period,  this  error  would  be  small  and  possibly 
negligible.    But  this  assumption  is  not  tenable. 


THE  RESPIRATORY  QUOTIENT  IN  DIABETES  337 

(d)  The  formation  of  sugar  from  protein  and  of  the  acetone  bodies 
from  fat,  and  their  elimination  and  consequent  withdrawal  from  the 
end  products  of  the  gas  exchange,  disturb  the  quotient.  Subtracting 
the  gross  equation  of  butyric  acid  from  the  equation  of  palmitic  acid, 
the  quotient  of  the  remainder  which  is  actually  burned  in  the  diabetic 
body  is  0.66.  If  all  the  fat  were  burned  only  to  the  stage  of  butyric 
acid,  the  respiratory  quotient  for  fat  in  the  diabetic  would  be  something 
like  0.66.  But  this  defect  is  not  total,  only  partial;  some  of  the  fat  is 
usually  completely  burned.  Therefore,  for  the  diabetic  the  respiratory 
quotient  lies  somewhere  between  0.66  and  0.69;  just  where  is  not  exactly 
determinable,  though  the  greater  the  amount  of  acetone  bodies  the 
lower  the  quotient.  When  butyric  acid  is  converted  into  beta-oxy- 
butyric  acid,  oxygen  is  added;  when  this  is  converted  into  diacetic 
acid,  oxygen  is  added  and  water  extruded;  when  this  is  converted  into 
acetone,  CO2  is  split  off.  Thus  when  one  molecule  of  butyric  acid  is 
converted  into  acetone,  one  molecule  of  oxygen  is  added  and  one  mole- 
cule of  carbon  dioxid  split  off,  and  the  respiratory  quotient  of  this  total 
process  is  1.  It  will  be  recalled,  however,  that  with  high  formation 
of  the  ketonic  bodies,  the  amount  of  acetone  formed  is  relatively  low. 
Therefore,  the  total  process  involves  the  binding  of  oxygen  that  has 
been  inspired,  and  the  quotient  is  lowered. 

On  the  basis  of  the  glucose  :  nitrogen  ratio  of  5  :  1,  1  gram  of 
protein  would  yield  0.8  gram  of  sugar  containing  0.32  gram  of  oxygen, 
while  the  gram  of  protein  from  which  it  was  derived  contained  at  the 
most  only  0.25  gram  of  oxygen.  This  oxygen  could  have  been  derived 
either  from  the  inspired  air  or  from  water.  But  as  the  molecule  of 
protein  contains  enough  hydrogen  (after  combining  with  all  the  nitrogen 
to  form  amino  groups)  to  form  this  amount  of  glucose,  we  are  justified 
in  the  conclusion  that  gaseous  oxygen  is  bound  in  this  formation  of 
sugar  from  protein.  One  gram  of  protein  contains  about  0.075  gram 
of  hydrogen;  of  this  not  over  0.025  would  be  needed  to  combine  with 
the  0.165  gram  of  nitrogen,  leaving  0.05  gram  of  hydrogen  to  enter 
into  the  formation  of  glucose  with  the  available  carbon  and  oxygen 
plus  gaseous  oxygen.  Just  how  much  oxygen  is  thus  bound,  cannot 
be  stated.  But  it  is  not  a  small  amount,  and  the  result  is  to  lower 
the  respiratory  quotient.  Assuming  the  oxygen  requirement  to  be 
500  to  600  grams  per  day,  if  a  diabetic  were  to  form  from  150  grams 
of  protein  120  grams  of  sugar  and  of  this  half  were  to  be  eliminated 
in  the  urine,  some  30  grams  of  oxygen  that  had  been  inspired  would 
be  eliminated  in  a  fixed  state.  If,  as  may  be  the  case,  butyric  acid  is 
also  formed  from  amino-acids  (though  this  must  be  a  very  secondary 
matter  in  diabetes),  this  too  would  involve  the  binding  of  oxygen. 
Thus  the  formation  of  sugar  from  protein  and  of  beta-oxy-butyric 
acid  and  diacetic  acid  from  fat  lower  the  respiratory  quotient  of  the 
diabetic.  And  the  total  result  of  these  cannot  be  much  opposed  by 
the  high  quotient  of  formation  of  acetone  from  diacetic  acid,  since  this 
occurs  to  such  a  small  extent. 
22 


338  METABOLISM 

To  summarize:  The  respiratory  quotient  of  protein,  0.8  in  the 
normal,  may  in  the  diabetic,  because  of  the  binding  of  oxygen  in  the 
glucose  that  is  eliminated  in  the  urine,  be  as  low  as  0.6;  the  respiratory 
quotient  of  fat,  0.71  in  the  normal,  may  in  the  diabetic  through  failure 
of  combustion  below  butyric  acid  and  through  binding  of  oxygen  to 
convert  butyric  acid  into  beta-oxy-butyric  and  diacetic  acids  be  as 
low  as  0.66.  It  is  necessary  to  bear  these  facts  in  mind  when  com- 
paring the  quotients  found  in  diabetes  with  those  obtained  in  normal 
individuals  on  the  same  diet. 

If  now  a  normal  individual,  assumed  freed  of  glycogen,  were  to 
be  placed  upon  a  protein-fat  diet  (75  to  125  grams  of  protein  and  200 
to  250  grams  of  fat),  the  respiratory  quotient  would  run  between  0.75 
and  0.78,  depending  upon  the  quantitative  relations  of  the  protein  and 
fat.  In  such  a  subject,  the  quotient  for  fat  is  0.71,  for  protein  0.8. 
A  respiratory  quotient  of  over  0.71  indicates,  therefore,  that  some 
carbohydrate  is  being  burned.  On  the  other  hand,  a  quotient  of  below 
0.71  does  not  prove  that  no  sugar  is  being  burned.  A  part  of  the  sugar 
formed  from  protein  may  be  burned;  but  if  a  larger  portion  be  elimi- 
nated, the  quotient  will  still  be  lower  than  the  figure  for  the  pure  com- 
bustion of  fat.  When  to  this  is  added  the  effect  of  the  non-combustion 
of  butyric  acid  (which  reduces  the  fat  quotient  to  0.66)  and  the  oxida- 
tion of  this  acid  to  beta-oxy-butyric  and  diacetic  acids,  it  is  clear  that 
there  may  be  a  considerable  combustion  of  sugar  with  a  reduction 
of  the  respiratory  quotient  below  0.7.  If  the  acidosis  be  low,  reduc- 
tion of  the  quotient  below  0.7  indicates,  of  course,  more  plainly  the 
defect  in  the  combustion  of  sugar  from  protein.  If  the  acidosis  be 
heavy,  the  higher  the  quotient  above  0.07  the  more  strongly  this  speaks 
for  the  retention  of  the  faculty  of  the  combustion  of  glucose.  If  the 
fat  catabolism  were  normal,  the  respiratory  quotient  ought  to  be 
inversely  proportional  to  the  glucose : nitrogen  ratio;  but  when  the 
fat  catabolism  is  badly  deranged,  this  operates  to  obscure  this  relation- 
ship. 

Coming  now  to  the  actual  quotients  observed  in  diabetes,  they  vary 
from  0.64  to  0.76,  the  average  for  cases  of  ordinary  severity  being 
0.73.  As  a  rule,  the  quotient  is  lower  the  more  severe  the  case;  but  to 
this  statement  striking  exceptions  occur  in  each  direction.  All  the 
cases  with  a  quotient  above  0.7  burn  sugar  to  greater  or  less  extent. 
A  quotient  of  0.7  in  a  diabetic  with  high  acidosis  speaks  for  a  greater 
sugar  utilization  than  the  same  quotient  in  a  diabetic  with  low  acidosis. 
But  even  the  diabetics  with  quotients  below  0.7  burn  some  little  sugar. 
The  quotient  for  protein,  where  0.8  gram  of  glucose  is  formed  from 
the  gram  of  protein  and  eliminated  entirely,  would  be  about  0.6.  The 
quotient  for  the  combustion  of  fat,  when  the  glycerol  is  converted  into 
sugar  and  lost  and  where  the  fatty  acid  is  only  burned  to  the  stage 
of  butyric  acid,  is  0.66,  and  even  this  will  be  lower  when  the  binding 
of  oxygen  in  the  oxidation  of  butyric  acid  is  considered.  Obviously, 
therefore,  we  cannot  necessarily  infer  that  a  diabetic  burns  none  of 


CONSIDERATION  OF  THE  TOTAL  METABOLISM  IN  DIABETES     339 

the  sugar  formed  from  protein  or  from  glycerol  unless  the  quotient  is 
below  0.63.  Such  very  low  quotients  are  very  rare,  and  indicate  how 
uncommon  it  is  to  have  the  defect  in  the  combustion  of  glucose  absolute. 
In  the  past,  too  exclusive  attention  has  been  given  to  the  glucose: 
nitrogen  ratio  in  the  interpretation  of  the  respiratory  quotient;  the 
fat  catabolism  as  expressed  in  the  acidosis  deserves  equal  attention. 
With  a  protein  input  of  125  grams  of  protein  per  day  and  fat  in  abun- 
dance, a  quotient  of  0.73  corresponds  probably  to  a  combustion  of  25 
to  50  grams  of  glucose  per  day.  By  calculation  also,  we  can  show  that 
the  combustion  of  20  grams  of  glucose  per  day  results  in  an  increase 
of  the  quotient  of  about  0.03  points.  There  is  some  evidence  that  sugar 
formed  from  protein  is  burned  better  than  glucose  ingested;  but  this 
conclusion  is  made  uncertain  by  our  inability  to  fix  the  amount  of 
glucose  derived  from  the  unit  of  protein. 


CONSIDERATION  OF  THE  TOTAL  METABOLISM  IN  DIABETES 

The  comparison  of  the  total  metabolism  of  the  diabetic  with  that 
of  the  normal  individual  is  very  difficult,  for  the  same  reasons  (though 
with  greater  force),  as  in  the  case  of  comparisons  between  different 
normal  individuals.  When  the  total  metabolism  of  normal  individuals 
is  measured,  very  striking  variations  are  found.  These  are  related  to 
age,  weight,  size,  type,  and  temperament.  The  total  weight  of  the 
body  ought  not  to  be  the  unit  of  metabolism,  as  the  fat  and  bones 
are  inert  in  this  sense.  The  heat  production  we  relate  to  the  body 
surface.  But  when  a  man  wastes,  the  ratio  of  weight  to  surface  may  or 
may  not  be  maintained.  If  an  individual  were  to  waste  in  muscle 
and  gain  in  fat,  the  unit  of  actual  metabolism  would  be  reduced,  though 
the  surface  of  radiation  remains  unaltered.  In  particular,  the  protein 
metabolism  is  subject  to  variations.  Then,  again,  individuals  differ 
greatly  in  muscular  repose,  even  in  enforced  rest.  And  as  the  values 
sought  to  be  determined  are  to  be  regarded  as  those  of  the  metab- 
olism of  the  state  of  rest,  this  causes  great  fluctuations.  Finally,  the 
methods  of  determination,  the  type  of  respiration  apparatus  or  calori- 
meter employed,  the  training  of  the  subject  in  the  apparatus  and  the 
adaptation  of  the  nervous  type  to  such  experiences,  introduces  another 
set  of  variables.  It  is,  therefore,  not  possible  to  make  strict  com- 
parisons between  individuals, .  but  only  between  averages  of  the  values 
obtained  with  diabetics  and  with  normal  subjects  chosen  to  correspond 
as  closely  as  possible  with  the  sick. 

In  the  beginning  of  this  discussion  of  diabetes,  it  was  stated  that 
the  total  metabolism  (heat  production)  of  the  diabetic  was  in  excess 
of  the  normal,  compared  as  fairly  as  was  possible.  This  excess,  for 
the  different  directions  of  measurement,  may  be  tabulated  as  follows, 
according  to  researches  of  the  Carnegie  Nutrition  Laboratory. 


340  METABOLISM 

Excess  over  normal  of: 

Heat  production  O-absorption  C02-elimination 

15  per  cent.  20  per  cent.  7  per  cent. 

The  apparent  discrepancy  between  the  great  excess  in  the  O-absorp- 
tion and  the  C02-elimination  is  due,  in  all  probability,  to  the  factor 
of  oxygen  combined  in  fixed  state  in  sugar  and  with  butyric  acid  to 
form  the  ketonic  acids.  Indeed,  the  discrepancy  between  the  absorp- 
tion of  oxygen  and  the  elimination  of  carbon  dioxid,  coupled  with  the 
absolute  increase  in  the  latter,  may  be  termed  characteristic  of  diabetes. 
The  formation  of  C02  is  relatively  and  absolutely  higher  in  severe  than 
in  mild  cases.  This  holds  true  also  for  the  oxygen  absorption  and 
heat  production,  though  to  less  extent.  The  more  severe  the  acidosis, 
the  more  marked  the  higher  values  in  oxygen  absorption,  C02  elimina- 
tion and  heat  production.  This  at  once  suggests  that  the  loss  occurs 
in  the  fat  catabolism.  It  was  at  first  assumed  that  these  increased 
values  might  be  simply  the  expression  of  the  specific  dynamic  action 
of  the  augmented  ingestion  of  protein;  a  calculation  of  this  possible 
factor,  however,  indicates  that  this  cannot  be  the  case,  it  is  not  large 
enough.  This  increased  heat  production  is  all  the  more  striking  when 
one  considers  that  the  formation  of  glucose  from  protein  is  an  endo- 
thermic  process,  so  that  the  heat  production  is  really  greater  than  it  is 
actually  measured  to  be.  In  a  crude  sense,  this  loss  of  heat  in  the 
diabetic  metabolism  may  be  compared  to  the  loss  of  heat  by  friction 
in  a  journal  with  ill-fitting  bearings. 

The  defects  of  the  diabetic  metabolism  as  affecting  the  utilization 
of  the  input  may  be  well  shown  in  tabular  form.  Let  us  arbitrarily 
define  four  degrees  of  severity:  mild,  moderate,  severe,  and  extreme. 
Let  the  diet  be  the  same  for  all — 125  grams  of  protein  and  200  grams 
of  fat,  with  a  total  heat  value  of  2300  Calories.  The  mild  case  will 
be  assumed  to  have  no  glucosuria  on  the  diet,  the  moderate  case  one 
of  25  grams,  the  severe  case  one  of  75  grams,  the  extreme  case  one 
of  100  grams  (a  total  glucosuria  on  the  glucose :  nitrogen  ratio  of  5  :  1). 
The  mild  case  will  be  assumed  to  have  no  acidosis,  the  moderate  case 
one  of  20  grams,  the  severe  case  one  of  50  grams,  the  extreme  case  one 
of  100  grams.  The  following  amounts  of  heat  in  Calories  would  then 
be  secured  from  the  diet  in  each  of  the  following  degrees  of  severity. 


Protein   . 

Fat    ...      . 

Mild 

.       500 
.     1800 

Moderate 

400 
1700 

Severe 

200 
1550 

Extreme 

100 
1300 

Total    .      . 

.     2300 

2100 

1750 

1400  Calories 

To  secure  the  heat  of  2300  Calories,  the  three  last  groups  would  need 
to  use  fat  and  protein  from  the  body,  or  else  the  ingestions  would  need 
to  be  increased,  as  follows: 


CONSIDERATION  OF  THE  TOTAL  METABOLISM  IN  DIABETES    341 


Mild 

Moderate 

Severe 

Extreme 

Protein  . 

.      .       125 

150 

150 

150  grams 

Fat    .      .      . 

.      .       200 

210 

240 

290 

This  all  under  the  assumption  that  the  extra  ingestions  of  protein  and 
fat  are  regarded  as  completely  burned.  In  short,  an  extreme  case  of 
diabetes  may  require  150  grams  of  protein  and  300  grams  of  fat  to 
secure  the  heat  that  a  normal  body  can  derive  from  125  grams  of  protein 
and  200  grams  of  fat.  In  addition  to  this  excess  of  metabolic  work,  the 
diabetic  has  to  contend  with  a  heavy  hyperglucemia  due  to  inability 
to  burn  the  glucose  formed  from  the  protein,  and  a  heavy  acidosis 
due  to  inability  to  burn  the  higher  fatty  acids  beyond  the  stage  of 
butyric  acid.  From  the  extreme  down  to  values  quite  within  the 
normal  are  to  be  found  all  shades  and  degrees  of  severity  in  diabetes; 
in  some  the  defect  in  the  protein  catabolism  being  most  prominent, 
in  others,  the  defects  in  the  acidosis  being  most  exaggerated.  The 
figures  in  the  above  tables  are  made  intentionally  rounded,  but  they 
illustrate  the  facts.  The  dynamic  action  of  protein  has  been  dis- 
regarded, since  the  maximum  ratio  for  the  production  of  glucose  from 
protein  has  been  employed.  Thus  at  the  worst,  the  diabetic  has  lost 
entirely  the  power  of  burning  sugar,  the  caloric  value  of  protein  is 
reduced  three-fourths,  and  the  caloric  value  of  fat  one-third.  Even 
in  this  state,  the  diabetic  could  adapt  himself  to  the  situation,  were 
it  not  for  the  hyperglucemia  and  the  acidosis.  It  is  not  alone  what 
the  diabetic  has  lost  in  faculties  of  combustion;  it  is  much  more  than 
that.  If  the  sugar  and  butyric  acid  were  mere  losses,  compensation 
could  be  attained.  But  they  both  establish  states  of  intoxication  within 
the  body,  and  it  is  to  these  that  the  diabetic  usually  succumbs,  unless 
by  intercurrent  disease.  In  diabetes  the  antibactericidal  properties  of 
the  blood  plasma  seem  to  be  lowered,  possibly  as  the  result  of  the 
action  upon  the  cells  of  the  hypertonic  concentration  of  glucose.  The 
idea  that  the  diabetic  serum  is  merely  an  improved  culture  medium 
on  account  of  the  increase  in  glucose  is  too  crude  to  serve  as  the 
explanation  of  the  increased  tendency  to  bacterial  infections  displayed 
in  this  disease. 

It  is  clear,  therefore,  that  the  coefficient  of  utilization  of  the  calories 
of  the  foodstuffs  may  fall  to  60  in  diabetes.  This,  however,  would  not 
seriously  hamper  the  life  of  the  diabetic,  though  it  naturally  limits 
greatly  his  function  of  adaptation.  It  is  not  loss  of  metabolism,  it  is 
autointoxication  that  is  the  menace  of  diabetes?***^ 


CHAPTER    V 

THE  FAT  METABOLISM 

Fat  plays  two  roles  within  the  body.  Fat  represents  the  ultimate 
form  of  the  storage  of  fuel,  and  the  depot  fats  are  quite  the  most  inert 
and  dead  of  any  of  the  body  structures.  On  the  other  hand,  fats  joined 
with  protein  and  in  complex  combinations  of  still  unknown  composi- 
tion, represent  the  most  essential  structures  in  cellular  protoplasm, 
cell  membranes,  and  in  the  central  nervous  system.  The  subjects  of 
fat  in  its  cellulometabolic  relations  and  fat  in  the  heat  metabolism 
are  almost  as  distinct  as  though  different  substances  were  under  con- 
sideration. Our  information  on  the  two  subjects  is  not  equal ;  we  know 
much  concerning  fat  as  fuel;  we  know  little  concerning  fat  in  cellular 
structure. 

The  fats  concerned  in  a  discussion  of  human  metabolism  are  the 
glycerids  of  palmitic,  stearic  and  oleic  acids  alone.  It  is  true  that 
small  amounts  of  butyric  acid  and  traces  of  caproic,  caprylic,  and 
capric  acids  exist  in  milk.  It  is  also  known  that  in  the  fats  of  other  animals, 
especially  in  fishes  and  in  the  marine  mammals,  other  fatty  acids  are 
present  and  also  other  alcohols  than  glycerol.  But  for  the  fat  metab- 
olism of  the  domesticated  animals  and  man  we  deal  essentially  only 
with  tristearin,  tripalmitin  and  triolein.  That  mixed  esters  occur, 
in  which  the  three  hydroxyl  groups  of  the  glycerol  are  replaced  by 
different  fatty  acids,  is  not  to  be  doubted,  either  for  the  depot  fats 
or  for  the  lipoids  of  the  central  nervous  system. 

Sources  of  Fats. — The  fats  of  the  body  have  two  sources:  The  fats 
ingested  with  the  diet;  and  the  fats  formed  in  the  body  from  sugar. 
In  the  one  instance  the  body  is  passive;  in  the  other  the  body  exercises 
selection  in  synthesis.  The  fats  of  the  diet  are  not  altered  in  the 
acts  of  digestion;  they  are  split,  the  glycerol  and  fatty  acids  absorbed, 
recombined  to  their  original  states  and  added  to  the  fats  of  the  body. 
Obviously,  therefore,  body  fat  thus  derived  will  vary  in  the  relative 
proportions  of  tripalmitin,  tristearin  and  triolein  precisely  in  accord- 
ance with  the  relations  of  the  three  fats  in  the  diet.  Fat  that  the  body 
synthesizes  from  sugar,  however,  has  a  constant  composition  with 
respect  to  the  relative  amounts  of  the  three  glycerids.  This  state 
of  facts  may  be  expressed  in  the  law  that  body  fat  derived  from  diet 
fat  is  specific  to  the  diet,  body  fat  formed  from  sugar  is  specific  to  the 
species.  Horses,  cattle,  sheep,  swine,  dogs,  fowl,  and  men  will  from 
a  uniform  protein-sugar  diet  form  body  fats  that  differ  widely  in  the 
relative  amounts  of  the  three  glycerids;  the  fat  of  cattle  and  sheep 
containing  a  high  amount  of  tristearin,  the  fat  of  swine,  dogs,  fowl, 


FORMATION  OF  FAT  FROM  SUGAR  343 

and  man  containing  less  tri stearin  and  more  triolein.  The  melting 
point  of  fat  may  be  regarded  as  the  point  in  temperature  where  the 
amount  of  triolein  present  is  able  to  dissolve  the  amounts  of  tripalmitin 
and  tristearin  present.  From  sugar,  therefore,  different  animals  form 
the  different  triglycerids  in  different  amounts.  Once  formed,  how- 
ever, the  body  apparently  cannot  alter  the  triglycerid;  it  cannot,  for 
example,  convert  tristearin  into  triolein  or  vice  versa.  Therefore, 
when  fats  are  ingested,  they  are,  following  resorption,  simply  added 
unchanged  to  the  fats  of  the  body.  It  is  thus  possible,  experimentally, 
to  modify  the  body  fat  of  an  animal.  The  fat  of  the  dog  formed  from 
sugar  contains  a  high  proportion  of  triolein  and  is  fluid  at  the  temper- 
ature of  the  body.  If  a  dog  be  starved  until  emaciated  and  then  fed 
exclusively  on  mutton  or  fat  beef,  the  mutton — or  beef — fat  will  be 
deposited  unchanged  in  the  tissues  of  the  dog,  giving  to  the  dog  an 
unnatural  solidity  of  subcutaneous  tissues.  If  a  female  dog  so  dieted 
and  transformed  into  a  "mutton  dog"  becomes  parturient,  the  milk 
will  be  found  to  contain  mutton  fat  instead  of  the  natural  fat  of  the 
dog's  milk.  In  a  word,  the  body  places  its  stamp  upon  the  fat  it  forms 
from  sugar.  It  can  form  any  one  of  the  three  triglycerids  from  sugar. 
But  once  formed,  either  by  itself  or  received  in  the  diet,  the  body 
cannot  convert  any  one  of  the  three  triglycerids  into  another.  There- 
fore, in  an  omnivorous  animal,  like  the  domesticated  dog  and  man, 
the  composition  of  the  body  fat  depends  upon  the  varying  extent 
to  which  the  body  fat  has  been  derived  from  the  diet  or  formed  from 
sugar.  The  fat  of  the  carnivora  will  depend  largely  upon  the  composi- 
tion of  the  diet;  the  fat  of  the  herbivora  will  be  most  specific  to  the 
species,  since  their  diet  consists  largely  of  carbohydrate  and  little  per- 
formed fat.  We  may  experimentally  feed  a  foreign  fat,  such  as  erucaic 
acid  (C22H44O2)  and  have  it  deposited  unchanged  in  the  tissues.  Lower 
fatty  acids,  such  as  are  ingested  in  milk,  are  certainly  convertible 
into  fat.  It  is,  however,  doubtful  if  any  fatty  acid  below  butyric  acid 
is  directly  convertible  (if  at  all)  into  fat;  it  must  first  be  converted 
into  sugar. 

Formation  of  Fat  from  Sugar. — The  mechanism  of  the  formation  of 
fat  from  sugar  is  unknown  from  the  experimental  point  of  view.  It 
is  quite  certain  that  when  the  fats  are  burned  in  the  body,  they  are 
gradually  built  down  to  butyric  acid.  It  is  on  the  contrary  equally 
certain  that  butyric  acid  can  be  built  up  to  fat.  We  may,  therefore, 
assume,  and  this  is  also  the  line  of  least  resistance  chemically,  that 
butyric  acid  is  the  stage  in  the  series  of  fatty  acids  at  which  the  transfer 
of  the  sugar  into  fatty  acid  occurs.  The  conversion  cannot  be  a  direct 
one,  the  glucose  must  first  be  split.  Now  lactic  acid  represents  the 
commonly  accepted  cleavage  product  of  glucose.  Lactic  acid  is  a 
three-carbon  chain,  while  butyric  acid  is  a  four-carbon  chain.  It 
might  be  assumed  that  the  lactic  acid  would  be  converted  into  pro- 
pionic acid  and  this  then  built  up  to  butyric  acid.    Thus: 


344  THE  FAT  METABOLISM 

CHs  CHs  CH3 

CHOH       ~>        CH2  -*        CH2 

COOH  COOH  CH, 

I 
COOH 

This  scheme  has  the  advantage  of  simplicity.  And  if  it  be  objected  that 
we  have  no  analogy  for  the  direct  addition  of  a  CH2  group,  it  may  be 
rejoined  that  since  all  the  schemes  for  the  formation  of  the  higher 
fatty  acids  from  butyric  acid  rest  upon  such  additions  of  CH2,  there 
can  be  no  reason  to  deny  this  in  the  case  of  propionic  acid.  Experi- 
mental work,  however,  has  given  a  hint  in  another  direction.  When 
sugar  is  digested  in  the  autolyzing  aseptic  liver,  lactic,  acetic  and 
butyric  acids  are  formed,  accompanied  by  the  evolution  of  hydrogen. 
From  this  it  may  be  inferred  that  the  lactic  acid  is  split  into  acetic 
aldehyd  and  formic  acid,  two  molecules  of  acetic  aldehyd  then  con- 
verted into  b-oxybutyric  aldehyd,  which  would  pass  in  turn  into 
butyric  acid.    Thus: 


CH3       CH3      CH3 

I 
CHOH 


CH3       CH3 


CHO      CHO       CHOH     CH2 
COOH      HCOOH    CH3        CH2       CH2 

CHO  J      CHO      COOH 

It  is  clear  that  unless  the  formic  acid  were  again  utilized  in  the  synthesis 
of  sugar,  this  scheme  entails  the  loss  of  one-third  of  the  carbon  content 
of  glucose  in  its  conversion  into  fat.  This  we  cannot  believe  to  be 
the  case,  it  seems  quite  certain  that  the  conversion  of  glucose  into  fat 
is  complete  so  far  as  the  carbon  is  concerned.  Further  uncertainty  is 
added  when  we  realize  that  acetic  aldehyd  when  ingested  is  burned, 
and  not  condensed  into  beta-oxy-butyric  aldehyd.  Obviously,  both 
schemes  present  difficulties,  yet  chemically  these  are  the  most  feasible 
that  we  possess.  However  the  steps,  the  fundamental  fact  stands 
that  the  body  can  convert  glucose  into  fat  in  almost  unlimited  amounts 
and  without  loss  of  energy. 

The  site  in  which  the  reaction  of  the  conversion  of  sugar  into  fat 
is  accomplished  is  not  known.  It  probably  does  not  occur  in  the 
muscles,  in  which  the  sugar  is  burned.  It  is  probable  that  it  occurs 
in  the  areolar  tissues.  It  is  finally  possible  that  it  occurs  in  the  liver. 
That  the  velocity  of  the  formation  of  fat  from  sugar  depends  normally 
upon  relations  of  concentration  of  glucose  in  the  body,  was  stated  in 
another  connection.  Apparently  the  body  forms  fat  from  sugar,  to  a 
high  degree  at  least,  only  when  the  capacity  of  the  body  for  the  storage 
of  glycogen  is  fully  utilized. 

When  fatty  acids  are  formed  from  glucose,  glycerol  must,  of  course, 
be  provided  for  them.     Glycerol  is  derived  also  from  glucose.     When 


FORMATION  OF  FAT  FROM  SUGAR  345 

fatty  acids  are  ingested,  glycerol  is  promptly  formed  to  combine  with 
them;  and  in  fact,  the  formation  of  glycerol  from  glucose  seems  very 
easy  of  accomplishment.    The  reaction  probably  proceeds  thus: 


Glucose 

Lactic  acid 

Tartronic  acid     Glyceric  acid 

Glycerose 

Glycerol 

CHO 

CHOH 

CHOH 

CH3 

CHOH 

COOH 

COOH            COOH 

1 

CHO 

CH2OH 
CHOH 

->    CHOH    ->    CHOH    -> 
COOH            CH2OH 

CHOH    -> 
CH2OH 

CH2OH 

CHOH     CH3 
CHOH     CHOH 
CH2OH    COOH 

As  previously  stated,  the  reaction  for  the  formation  of  glycerol 
from  glucose  is  reversible,  and  there  can  be  little  doubt  that  glycerol  is 
normally  catabolized  via  sugar.  The  site  of  the  formation  of  glycerol 
from  glucose  is  held  to  be  the  liver. 

When  the  fat  of  the  diet  reaches  the  lymph  spaces  of  the  submucosa 
of  the  intestine,  it  is  believed  to  be  entirely  in  the  neutral  state,  i.  e., 
the  recombination  of  the  glycerol  with  the  fatty  acids  is  completed 
in  the  act  of  resorption.  The  fat  is  then  collected  in  the  branches 
of  the  lacteal  system  and  transported  to  the  thoracic  duct.  In  the 
contents  of  this  duct  the  fat  is  largely  in  a  state  of  emulsification.  The 
processes  of  fat  digestion  and  resorption  are  relatively  slow  and  are 
probably  not  completed  in  less  than  eight  hours  after  the  ingestion 
of  a  meal;  and  thus  fat  is  being  poured  into  the  venous  circulation 
through  the  thoracic  duct  during  some  five  or  six  hours.  Since  the 
fat  of  a  meal  will  rarely  exceed  75  grams,  even  where  fat  replaces  the 
carbohydrates  of  the  diet,  it  is  clear  that  under  the  most  extreme 
conditions  not  over  0.25  gram  of  fat  will  be  poured  into  the  circulation 
per  minute.  This  fat,  as  a  rule,  is  not  carried  in  the  blood  in  a  state 
of  emulsification,  as  it  exists  in  the  fluid  of  the  thoracic  duct.  The 
blood  contains  about  1  per  cent,  of  fat,  as  a  rule;  it  can  hold  double 
that  amount  in  solution.  The  fat  exists  in  the  blood  plasma  in  some 
complex  chemical  combination,  (quite  certainly  not  with  protein),  in 
which  state  it  is  not  only  soluble  but  apparently  diffusible.  It  is  clear, 
therefore,  that  since  the  blood  can  hold  at  least  1  per  cent,  of  fat  in 
this  state  of  solution,  the  maximum  fat  ration  of  a  meal  can  be  carried 
in  this  state  in  the  blood  in  any  one  moment.  This  explains  why 
lipemia  (the  appearance  of  a  fat  emulsion  in  the  blood  plasma)  is,  as 
a  rule,  not  observed  following  even  excessive  ingestions  of  fat.  Upon 
what  chemical  substance  this  capacity  of  the  blood  plasma  for  the  solu- 
tion of  the  neutral  fat  depends,  is  not  known.  The  fact  is,  however, 
crucial  to  our  conception  of  the  fat  metabolism.  We  assume  that 
this  soluble  state  of  fat  in  the  blood  represents  the  reaction  state  of 
fat.    We  assume  that  fat  is  thus  transported  to  the  areolar  cells,  through 


3-4G  THE  FAT  METABOLISM 

whose  walls  it  diffuses;  the  combination  is  there  split  and  the  neutral 
fat  deposited  as  depot  fat.  Whenever  fat  is  burned,  we  assume  that 
this  state  of  solution  is  the  state  of  reaction.  When  the  fats  are  needed 
and  must  be  recalled  from  the  depots,  we  assume  that  they  are  again 
converted  into  the  state  of  solution  through  this  complex  combina- 
tion and  transported  to  organs  or  tissues  of  combustion;  or  if  fat  be 
burned  in  the  areolar  tissues,  it  is  first  converted  into  the  soluble  state 
before  being  available  for  the  processes  of  combustion.  This  state  of 
combination,  of  solubility  and  diffusibility,  is  in  a  word  the  conditio 
sine  qua  non  of  chemical  reaction  on  the  part  of  the  neutral  fats.  The 
blood  and  the  tissues,  especially  the  liver,  may  contain  traces  of  free 
glycerol  and  fatty  acids.  The  fats  in  the  depots  are  within  cells,  in 
the  strict  sense  of  the  word,  as  truly  as  in  the  case  of  fatty  infiltration 
of  the  liver.  When  depot  fat  is  drawn  upon,  it  is  that  stored  in  the 
liver  that  is  first  utilized,  precisely  as  in  the  case  of  glycogen.  The 
conversion  of  the  neutral  fat  of  the  depot  cells  into  the  soluble  complex 
we  relate  to  the  chemical  functions  of  these  cells,  just  as  we  relate  the 
conversion  of  glycogen  into  sugar  to  the  chemical  functions  of  the  liver 
cells.  From  this  point  of  view  it  is  obvious  that  the  cells  of  the  areolar 
connective  tissues  occupy  a  position  of  high  metabolic  importance. 


THE    ANABOLISM   OF   FAT 

Four  lipoid  groups  are  included  in  the  anabolized  fats.  These  are  the 
protein-fat  complex;  the  phosphatids;  the  sterins;  and  the  cutaneous 
lipoids.  Future  investigations  may  indicate  that  this  separation  into 
groups  is  not  based  upon  a  chemical  foundation.  And  even  today 
the  classification  is  largely  one  of  convenience,  though  certain  chemical 
differentiations  seem  to  exist.  All  the  anabolized  lipoids,  in  whatever 
form  and  wherever  present,  are  derived  from  the  neutral  fats.  We 
assume  that  the  neutral  fats,  in  soluble  and  diffusible  state,  are  carried 
to  the  specialized  cells  of  the  body,  there  to  be  transformed  into  the 
complex  combinations  that  play  so  important  a  role  in  physiological, 
pharmacological  and  bacteriological  reactions.  These  lipoids  are 
present  in  cell  membranes,  in  protoplasm,  in  nuclei,  in  the  circulating 
fluids  and  in  the  secretions.  It  is  doubtful  if  they  are  ever  to  be  regarded 
as  excrementa,  even  in  the  secretions  of  the  sebaceous  glands  or  in 
the  bile.  They  exist  in  plants  to  quite  as  widespread  an  extent  as  in 
animals.  Some  of  the  lowest  members  of  the  lipoids  are  relatively 
simple. in  their  makeup;  others  are  extremely  complex  and  of  these  we 
possess  very  little  real  information.  Some  lipoids,  even  unassociated 
with  protein,  seem  to  possess  biological  specificity.  They  are  all  more 
or  less  pronouncedly  colloidal,  and  present  to  a  striking  degree  the 
phenomenon  of  adsorption.  To  their  fatty  nature  and  to  their  colloidal 
properties  are  due  in  large  part  the  difficulties  of  a  chemical  study  of 
these  lipoids. 


THE  ANABOLISM  OF  FAT  347 

A  general  survey  of  the  chemical  and  physico-chemical  properties 
of  the  lipoids,  as  applied  to  their  cellular  relations  (in  the  membrane 
and  protoplasm),  indicate  two  directions  in  which  they  might  be 
expected  to  (and  demonstrably  do)  influence  fundamental  processes 
of  function.  The  presence  of  lipoids  in  a  cell  membrane  is  associated 
with  the  quality  of  semipermeability;  and  the  presence  of  lipoid  in 
protoplasm  brings  into  operation  the  law  of  partition.  We  have  many 
illustrations  of  the  property  of  semipermeability  in  cell  membranes, 
whereby  certain  substances  or  elements  are  permitted  to  pass  and 
others  are  restrained;  and  we  are  able  to  prepare  inorganic  membranes 
that  present  these  phenomena  to  a  striking  extent.  So  far  as  living 
or  dead  cells  are  concerned,  this  matter  is  not  yet  upon  a  sound  experi- 
mental basis ;  but  we  will  not  go  far  wrong  when  we  relate  this  property 
to  the  lipoid  complex  in  the  cell  membrane.  With  regard  to  the  applica- 
bility of  the  law  of  partition  to  biological  relations,  we  are  on  more 
explored  ground.  Protoplasm  is  a  two-phase  system,  consisting  of 
water  in  which  are  suspended  protein-lipoid  complexes  and  in  which 
are  dissolved  salts.  Salts  and  ions  are  not  only  dissolved  in  the  water 
but  are  also  combined  with  protein;  sugar  and  other  crystalloid  sub- 
stances are  present,  both  free  and  combined.  But  in  so  far  as  the  law 
of  partition  is  concerned,  it  is  the  lipoids  that  dominate  the  scene. 
This  protoplasm,  by  virtue  of  the  presence  of  lipoids,  becomes  a  solvent 
to  substances  that  are  in  themselves  insoluble  in  water.  It  is  just  as 
though  we  had  a  saturated  solution  of  ether  in  water.  Such  a  solution 
will  dissolve  many  substances  that  are  insoluble  in  water.  A  great 
many  pharmacological  substances,  and  apparently  many  biological 
and  bacteriological  substances,  are  lipo-soluble,  i.  e.,  will  be  taken  up 
by  a  lipoid  or  by  a  water  or  protoplasm  containing  lipoid.  It  is  for 
this  reason  that  neutral  fats  themselves  are  taken  up  by  protoplasm. 
In  the  intricate  physiology  of  the  cell  these  reactions  undoubtedly  play 
a  leading  role.  And  from  the  broadest  point  of  view,  the  modifications 
that  the  colloidality  of  a  system  impose  upon  the  purely  chemical 
reactions  in  the  system  ought  always  to  be  kept  in  mind. 

(a)  The  Fat-protein  Combination. — Cells  contain  apparently  neutral 
fat  combined  with  protein.  If  a  gland,  like  the  kidney,  be  completely 
extracted  with  fat  solvents  and  then  digested  with  trypsin,  a  subsequent 
extraction  will  yield  a  goodly  amount  of  fatty  substance.  Some  of 
these  are  phosphatids  and  sterins,  but  a  portion  consists  of  neutral 
fat.  The  amount  of  such  fat  in  combination  with  protein  is  not  large. 
Nor  is  the  combination  confined  to  the  cells,  but  exists  in  the  blood 
serum.  Beyond  these  few  facts,  nothing  is  known  of  the  fat-protein 
complex. 

(b)  The  Phosphatids. — These  are  the  best  known  of  the  lipoids. 
Some  that  are  well  known  contain  an  amino  group.  In  their  simplest 
form  they  may  be  defined  as  lipoids  in  which  two  molecules  of  a  higher 
fatty  acid  are  combined  with  glycerol-phosphoric  acid,  to  which  is 


348  THE  PAT  METABOLISM 

bound  an  amino  body.  Glycerol-phosphoric  acid  is  a  stereoisomeric 
substance  and  has  the  formula: 

CH2OH 

I 
CHOH 

I 
CH2.O.P03H2. 

Therefore,  the  general  formula  for  the  simplest  monamino-mono- 
phosphatid  would  be: 

CH20    —    fatty  acid 

CHO  •   —    fatty  acid 

CH20 

OH— P   =  O. 

R  — O 

The  best-known  representative  of  this  type  is  lecithin,  widely  prevalent 
in  animal  tissues.  In  lecithin  may  be  found  two  molecules  each  of 
stearic,  palmitic  or  oleic  acid  or  any  two  of  the  three;  thus  we  have, 
for  example,  a  distearyl  lecithin,  a  stearyl-oleyl  lecithin,  etc.  The 
amino  base  combined  with  the  phosphoric  acid  in  common  lecithin 
is  cholin, 

CH2  —  CH2(OH) 

N-(CH3)3 

OH 

Cholin  is  tri-methyl-oxy-ethyl-ammonium  hydroxid,  and  the  structure 
is  made  clear  by  the  equation: 

CH3 

A/CHs 

N^        CH3 

^  CH2  —  CH2OH 
OH 

Cholin  is  formed  by  the  union  of  glycol, 


with  tri-methyl-amin, 


CH2OH 
CH2OH 

CH3 

N— CH3 

CH3 


THE  ANAB0L1SM  OF  FAT  349 

and  is  found  free  in  some  plants,  in  which  lecithins  are  very  common. 
Thus  the  equation  of  distearyl  lecithin  would  be:  J\ 

CH2.O.OC.Cl7H36 
CHO.O.OC.C17H35 
CH2  — O 

HO  — P  =  O 

CH2  —  CH2  —  O 

/ 
N— (CH3)2 

XOH 

In  the  lecithins  of  plants  other  bases  related  to  cholin  and  probably 
derived  from  it,  may  replace  it.  Whether  neurin,  which  has  been 
recovered  from  brain  substance  and  which  is  probably  trimethyl- 
vinyl-ammonium  hydroxid,  exists  performed  in  lecithin  is  very  doubtful. 
All  the  lecithins  in  the  higher  animals  seem  to  contain  cholin.  Yet 
lecithins  exist  with  only  one  methyl  group.  Thus  b-kephalin,  recovered 
from  the  human  brain,  is  dioxy-stearyl-monomethyl  lecithin. 

More  complex  lecithins  are,  however,  known.  Thus  there  is  evidence 
for  the  existence  of  monamino-diphosphatid,  diamino-monophos- 
phatid,  and  of  diamino-diphosphatid.  In  these  larger  complexes  more- 
over, greater  differentiation  occurs  in  other  directions.  Firstly,  fatty 
acids  other  than  those  of  the  normal  series  or  oleic  acid  enter,  some 
resembling  the  linoleic  and  linolenic  acids.  Secondly,  sugars  enter 
into  the  complex,  especially  d-galactose.  These  more  complex  forms 
of  phosphatid  are  found  largely  in  the  central  nervous  system  and 
of  them  d-galactose  seems  to  be  an  invariable  component,  though 
d-glucose  may  also  be  met  with.  One  of  the  most  complex  diphos- 
phatids  known  has  been  isolated  from  heart  muscle.  It  is  the  com- 
plexity of  these  phosphatids  and  also  the  occurrence  side  by  side  of 
different  phosphatids,  aided  by  their  colloidal  and  lipoidal  properties, 
that  renders  the  subject  of  the  chemical  study  of  the  brain  substance 
so  unsatisfactory. 

To  what  extent  the  body  forms  its  own  cholin  and  glycerol-phos- 
phoric  acid  and  whether  it  is  at  all  dependent  upon  these  substances 
derived  from  the  alimentary  tract  is  not  known.  The  body  can  form 
glycerol-phosphoric  acid,  and  it  is  scarcely  to  be  believed  that  it  is 
dependent  upon  the  diet  for  its  cholin. 

(c)  The  Sterins. — Under  this  name  we  group  all  the  lipoids  that 
resemble  the  cholesterols.  Like  the  phosphatids,  sterins  are  very 
widely  distributed  in  plants  and  animals.  So  far  as  the  higher  animals 
are  concerned,  however,  while  all  the  body  cells  and  fluids  contain 
sterin,  it  seems  to  be  in  but  one  form,  cholesterol.  The  cholesterol 
isolated  from  nervous  tissue,  from  gallstones,  from  red  corpuscles,  and 
from  the  blood  plasma  is  identical  with  that  isolated  from  the  yolk 


350  THE  FAT  METABOLISM 

of  egg.  Related  bodies  are  to  be  found  in  the  sebaceous  secretions 
and  in  the  wool  fat  of  many  animals.  The  common  form  of  cholesterol 
is  a  monovalent,  unsaturated  secondary  alcohol,  with  a  ring  structure 
resembling  that  of  the  terpens.  There  is  but  one  hydroxy  1  group. 
The  substance  has  a  formula  something  like  the  following: 

(CH2)2.CH.CH2.CH2.Ci7H26.CH  =  CHg 

/\ 

H2C       CH.2 
\/ 
»  CH(OH) 

It  combines  with  fatty  acids  to  form  esters.  In  the  body  both  the 
free  alcohol  and  esters  are  to  be  found.  Thus  in  the  bile  and  red  blood 
cells  it  is  free;  in  the  brain  substance,  however,  it  is  usually  combined 
with  a  fatty  acid.  That  cholesterol  is  formed  from  the  higher  fatty 
acids  in  the  body  is  scarcely  more  than  a  theoretical,  though  a  reason- 
able, assumption.  It  is,  however,  possible  that  it  is  derived  from  the 
diet,  passing  unchanged  through  the  alimentary  tract. 

(d)  The  Sebaceous  Lipoids. — In  the  secretions  of  the  skin  and  scalp 
are  many  lipoidal  bodies,  including  both  phosphatids  and  sterins. 
These  are  formed  as  specific  secretory  products  of  glands,  and  are  to 
be  regarded  as  metabolic  products,  and  in  nowise  as  excrementa. 
Though  of  greater  importance  to  the  fur-  and  feather-bearing  animals 
than  to  man,  yet  in  all  they  have  the  same  function — to  enable  the 
body  to  shed  water  and  to  reduce  radiation  of  heat. 


THE   CATABOLISM   OF   FAT 

The  catabolism  of  the  fats  includes  the  building  down  of  the  complex 
lipoids  that  bear  such  important  functions  in  the  body,  and  the  com- 
bustion of  neutral  fat  and  fatty  acids.  Of  the  modus  operandi  of  the 
catabolism  of  the  phosphatids  and  sterins  we  are  not  well  informed. 
From  all  that  we  know  the  phosphatids  are  split  by  lipase  into  their 
component  fractions,  each  then  to  go  to  the  fate  of  its  group:  the  fatty 
acids  are  burned;  the  d-galactose  and  glycerol  are  converted  into 
d-glucose;  the  phosphoric  acid  is  eliminated  as  an  inorganic  salt;  and 
the  cholin  is  probably  split  into  its  components,  glycol  and  tri-methyl- 
amin,  the  first  of  which  would  be  burned  while  the  second  is  apparently 
eliminated  in  the  urine,  the  source  of  the  traces  of  tri-methyl-amin 
normally  present  there.  As  to  the  fate  of  cholesterol,  we  know  less. 
Human  feces  contains  a  substance  termed  koprosterin,  apparently 
a  dihydro-cholesterol;  horse  feces  contain  a  similar  substance  termed 
hippo-koprosterol.  These  are  supposed  to  represent  reduction  products 
of  cholesterol  of  the  bile,  the  results  of  bacterial  action.  Recent  work 
has  made  it  probable,  however,  that  these  substances  are  derived 
from  the  diet  and  not  from  the  cholesterol  of  the  bile.  Human  feces 
contain  unchanged  cholesterol,  and  some  is  certainly  resorbed  in  the 


THE  CATABOLISM  OF  FAT  351 

small  intestine.  That  the  cholic  acid  of  the  body,  present  in  the 
biliary  acids,  is  derived  from  cholesterol,  is  very  probable,  as  elucidated 
in  the  discussion  of  the  bile. 

The  Combustion  of  Fat. — The  catabolism  of  fat  resolves  itself  into 
combustion.  Initial  to  combustion  is  hydrolytic  cleavage  of  the  neutral 
fat  into  fatty  acid  and  glycerol.  In  the  case  of  the  complex  fats  of  the 
anabolic  series,  we  assume  that  in  the  autolysis  of  the  cells  containing 
them,  these  complex  combinations  are  split  into  their  several  compo- 
nent parts.  In  the  case  of  the  lipo-protein  complex,  in  the  autolysis 
of  the  cells  these,  too,  undergo  cleavage.  For  these  hydrolytic  cleav- 
ages, in  the  velocity  in  which  they  occur  in  the  body,  we  hold  the 
lipases  responsible.  In  the  case  of  the  depot  fats,  we  assume  that 
the  inert  fats  are  first  converted  into  the  soluble  and  diffusible  state. 
Whether  they  are  then  carried  to  the  liver  to  be  acted  upon  by  the 
fat-splitting  ferment,  or  whether  this  enzyme  acts  upon  the  fat  in  the 
areolar  tissues,  is  not  known.  But  under  all  circumstances,  the  reac- 
tion of  cleavage  precedes  the  reaction  of  combustion. 

The  fraction  of  glycerol  is  not  burned  directly,  we  believe,  but  is 
converted  into  sugar  and  joins  the  glucose  content  of  the  body.  The 
glycerol  of  1  gram  of  neutral  fat  will  form  over  0.1  gram  of  glucose. 

The  combustion  of  the  fatty  acids  of  the  saturated  series  is  now 
fairly  well  understood.  It  will  be  recalled  that  the  carbons  in  the 
chain  of  such  a  fatty  acid  are  designated  from  below  upward,  above 
the  carboxyl,  in  the  order  of  the  letters  of  the  Greek  alphabet,  alpha, 
beta,  etc.  Now  in  the  oxidation  of  such  a  fatty  acid,  the  point  of  attack 
is  the  beta  carbon,  the  second  one  above  the  carboxyl  group.  The 
oxidation  at  this  point,  passing  through  two  known  intermediary 
reactions,  results  in  the  splitting  off  of  two  atoms  of  carbon,  water  and 
carbon  dioxid  being  formed,  with  the  consequent  shortening  of  the 
chain  by  two  carbons.  And  this  process  is  repeated  until  butyric  acid 
is  reached.  Oxidations  attacking  the  alpha  carbon  are  known,  but 
apparently  they  do  not  occur  in  the  normal  combustion  of  fats.  Obvi- 
ously, only  fatty  acids  containing  an  even  number  of  carbons  in  the 
chain  could  be  thus  carried  to  butyric  acid.  And  valerianic,  pelargonic 
and  margaric  acids,  which  the  body  can  burn,  must  accordingly  be 
burned  in  some  other  way  than  to  butyric  acid.  This  scheme  of  com- 
bustion deserves  a  detailed  illustration.    Thus  for  stearic  acid: 


352  THE  FAT  METABOLISM 

Stearic  acid  Palmitic  acid 

CH3  CH3  CH3  CH3 

1  1  1  T 

CH2  CH2  CH2  CH2 

CH2  CH2  CH2  CH2 

CH2  CH2  CH2  CH2 

CH2  CH2  CH2  CH2 

CHj  CH2  CH2  CH2 

CH2  CI12  CH2  CH2 

CH2  CH2  CH2  CH2 

1  T  1  T 

CH2  CH2  CH2  CH2 

T  1  1  T 

CH2  CH2  CH2  CH2 

1  .1  1  ■  T 

CH2  CH2  CH2  ch2 

1  1  1  T 

CH2  CH2  CH2  CH2 

1  1  1  T 

CH2  CH2  CH2  CH.2 

1  1  1  T 

CH2  CH2  CH2  CH2 

CH2  CH2  CH2  CH2 

|9     CH2      +  O    =     CHOH  +0    =  CO   +  4  O    =     COOH 


CH2  CH2 

I  I 

COOH  COOH  COOH  H20 


2C02 


+ 
H20 

In  like  manner  palmitic  acid  yields  myristic  acid;  this  yields  lauric 
acid;  this  in  turn  furnishes  capric  acid;  the  next  formed  is  caprylic 
acid;  this  yields  caproic  acid;  and  this  finally,  on  oxidation  of  its  beta 
carbon  yields  butyric  acid,  as  follows : 

Caproic  acid  Butyric  acid 

CH3  CH3  CH3  CH3 

CH2  CH2  CH2  CH 

II  1  T 

CH2  CH2  CH2  C 


2 
Hi 


CH2   +  O    =  CHOH+  O    =     CO  +  4  O  =  COOH 
CH2  CH2  CH2  2  CO2 

COOH  COOH  COOH  H20 


+ 
H20 


At  this  point  the  process  suffers  a  deflection,  and  this  is  a  matter 
of  great  importance,   involving   the  pathogenesis   of  acidosis.     The 


THE  CATABOLISM  OF  FAT 


353 


butyric  acid  is  partially  oxidized  at  its  beta  carbon,  to  form  beta-oxy- 
butyric  acid;  this  substance  is  further  oxidized  at  the  same  point,  so 
that  the  beta  carbon  is  now  completely  oxidized  and  aceto-acetic  acid 
is  formed.  This  is  then,  by  the  addition  of  water,  split  into  two  mole- 
cules of  acetic  acid,  which  through  formic  acid  is  easily  oxidized  to 
carbon  dioxid  and  water.  At  the  same  time  a  side  reaction  occurs 
normally  to  a  slight  degree,  whereby  aceto-acetic  acid  is  reduced  to 
acetone;  (di-methyl  ketone)  through  the  splitting  off  of  a  molecule 
of  carbon  dioxid.     Thus: 


Butyric  acid 

CH3 

P    CH2   + 
a    CH2 

b-oxy-butyric  acid          Aceto-acetic  acid 
CH3                               CH3 

0 

=   CHOH  +  0   = 

1 
CH2 

1 

l 
=  CO 

1 

CH2 

+  H20  - 

COOH 

COOH 

COOH 

Acetic  acid 

CH3 

Formic  acid 

End  products 

C02    H20 

COOH 

->        HCOOH 

*"* 

C02    H20 

CH3 

C02    H20 

COOH 

~*        HCOOH 

-» 

C02    H20 

A  side  reaction  occurs,  with  the  reduction  of  aceto-acetic  acid  to 
acetone : 

CH3  CH3 

CO  CO 


CH2 


OOH 


CH3 

co2 


Under  normal  conditions,  there  is  but  a  trace  of  the  product  of  this 
side  reaction  in  the  urine,  and  none  in  the  expired  air.  As  the  amount 
of  fat  burned  by  the  body  is  augmented  this  side  reaction  increases, 
but  in  greatly  more  than  direct  proportion,  possibly  in  the  proportion 
of  the  square  of  the  unit  of  increase  in  the  fat  combustion.  For  illustra- 
tion, if  a  body  burn  but  50  grams  of  fat  per  day,  there  will  be  only  a 
trace  of  acetone  formed;  if  now  the  body  burn  200  grams  of  fat,  the 
acetone  formed  will  not  be  four  times  the  amount  recovered  when  the 
body  burned  50  grams,  but  rather  sixteen  or  more  times.  To  this  general 
rule  there  are  exceptions,  in  normal  individuals  as  well  as  in  diabetics. 
But  for  the  most  part  the  rule  holds,  that  increase  in  the  fat  combus- 
tion is  associated  with  a  very  disproportionate  increase  in  the  side 
reaction,  the  formation  of  acetone. 

An  earlier  and  somewhat  more  simple  conception  of  the  oxidation 
from  the  stage  of  beta-oxy-butyric  acid  ran  as  follows: 
23 


354  THE  FAT  METABOLISM 

b-oxy-butyric  acid  Acetic  acid 

CH3  CH8 

8    CHOH  COOH 

ex.    CH2  CHj 


COOH  C 


OOH 

Obviously,  according  to  this  scheme,  oxidation  occurred  at  the  beta 
carbon  and  reduction  at  the  alpha  carbon,  with  cleavage  between 
them.  According  to  this  scheme  aceto-acetic  acid  and  acetone  would 
occur  never  in  the  normal  combustion  of  fat.  Since  they  are  always 
present,  acetone  in  substance  and  aceto-acetic  acid  necessarily  pre- 
ceding it,  the  scheme  first  stated  would  receive  the  preference,  unless 
it  could  be  demonstrated  that  the  trace  of  acetone  present  in  normal 
urine  might  have  been  otherwise  derived.  This  will  be  discussed  under 
the  acetone  complex. 

The  oxidation  of  triolein  is  less  well  understood,  and  chemically 
is  not  so  simple.    It  will  be  recalled  that  oleic  acid  has  the  equation: 

CsHi7\  /H 

>c  =  c< 

H  r  \CH2)7COOH 

Now  when  unsaturated  fatty  acids  are  oxidized  by  chemical  agents, 
they  tend  to  be  split  at  the  double  linkage  between  the  two  carbons, 
and  this  would  form  from  oleic  acid  one  molecule  of  pelargonic  acid 
(CsH17COOH),  and  one  of  azelaic  acid  (COOH.C7H14.COOH);  one  a 
saturated  fatty  acid,  the  other  unsaturated,  each,  however,  with  an 
uneven  number  of  carbon  atoms  in  the  chain.  In  the  body,  however, 
judging  by  experiments  with  the  liver,  no  such  reaction  is  done,  but 
instead  caproic  acid  is  formed.  It  is,  therefore,  to  be  inferred  that  the 
organism  is  able  to  shift  the  location  of  the  double  linkage  to  such  a 
point  that  the  cleavage  in  the  reaction  of  oxidation  will  yield  caproic 
acid.     This  could  be  done  as  follows: 


Ii7\  /H  CeHnv  /H 

>c  =  c<  -  >c  =  c< 

H/  x(CH2)7COOH  H/  \CH,),n< 


Cleavage  at  the  site  of  the  double  linkage  with  oxidation  of  the  two 
carbons  would  yield  caproic  acid  (C5Hn.COOH),  and  COOH.(CH2)io. 
COOH,  which  by  reduction  and  cleavage  would  form  two  further 
molecules  of  caproic  acid.  This  caproic  acid  would  then  be  open  to 
oxidation  at  the  beta  carbon,  with  the  formation  of  butyric  acid.  This 
may  not  be  the  exact  scheme  but  some  such  series  of  cleavages  must 
be  carried  out,  since  we  know  that  in  diabetes  oleic  acid  yields  more 
acetone  than  do  palmitic  and  stearic  acids,  and  it  must,  therefore, 
pass  through  the  stage  of  butyric  acid, 


THE  CATABOLISM  OF  FAT  355 

These  reactions  we  assume  are  the  results  of  the  activities  of  oxida- 
tion ferments.  It  seems  reasonable  to  separate  the  series  before  the 
stage  of  butyric  acid  from  the  reactions  subsequent  to  that  stage. 
Apart  from  the  reasons  for  this  separation  suggested  by  the  equations, 
there  is  a  positive  fact  in  its  favor,  namely,  that  in  diabetes  there 
is  no  difficulty  in  the  oxidation  of  the  higher  fatty  acids  to  the  stage 
of  butyric  acid,  but  great  difficulty  in  the  oxidation  of  butyric  acid. 
As  to  the  site  of  these  oxidations,  it  is  certain  that  they  occur  actively 
in  the  liver,  but  it  is  in  nowise  demonstrated  that  they  occur  there 
alone.  There  is,  however,  some  evidence  that  these  reactions  do  not 
occur  in  the  muscles.  If  they  occur  outside  of  the  liver,  therefore,  it 
must  be  in  the  areolar  tissues  of  the  body.  And  under  such  an  inter- 
pretation, the  areolar  tissues  act  not  only  as  the  depots  for  the  storage 
of  fat,  but  also  as  the  site  of  their  combustion. 

Important  from  many  points  of  view  is  the  fact  that  the  body  does 
not  burn  much  fat  so  long  as  glucose  is  available.  Not  until  the  glycogen 
stores  of  the  body  become  reduced  does  the  body  burn  its  fat.  This 
is  in  a  direct  sense  the  converse  of  the  situation  in  the  formation  of 
fat,  which  does  not  occur  until  the  glycogen  depots  are  stocked. 

The  Formation  of  Sugar  from  Fat. — In  the  discussion  of  the  combustion 
of  fat,  no  mention  was  made  of  the  possibility  that  fat  might  be  burned 
via  sugar.  All  the  chemical '  and  experimental  data  bearing  on  the 
utilization  of  fat  in  the  higher  animals  indicate  that  it  is  burned  as 
outlined;  and  though  in  some  points  the  demonstration  is  not  positive, 
yet  on  the  whole  the  scheme  is  satisfactory.  The  reasons  for  an  assumed 
conversion  of  fat  into  sugar  rest  upon  two  wholly  unlike  propositions. 
One  is  the  general  rule  that  in  the  plant  world  the  reaction  sugar  t^  fat 
is  reversible.  The  second  is  that  in  clinical  diabetes  sugar  seems  some- 
times to  be  eliminated  in  amounts  so  large  as  to  make  difficult  its 
derivation  from  protein  and  carbohydrate  in  the  diet  and  tissues  of 
the  subject.  The  biological  argument  for  reversion  does  not  apply 
to  a  concrete  question,  attractive  as  a  general  rule  always  is;  the  forma- 
tion of  sugar  from  fat  must  be  demonstrated  experimentally.  All 
efforts  to  demonstrate  this  reaction  physiologically  have  failed.  If 
it  should  prove  to  be  true  in  diabetes  (the  question  is  fully  discussed 
under  that  heading),  that  with  the  subject  on  a  carbohydrate-free 
diet,  subsisting  on  known  rations  of  protein  and  fat,  the  elimination 
of  so  much  glucose  in  the  urine  occurs  as  not  to  be  derivable  from  the 
protein  undergoing  catabolism,  and  such  elimination  could  be  shown 
to  be  maintained  so  long  as  to  exclude  positively  any  stored  carbo- 
hydrates in  the  body — then  obviously  the  conclusion  would  follow  cer- 
tainly that  the  diabetic  had  formed  sugar  from  fat.  And  if  this  were 
to  be  shown  to  hold  for  the  diabetic,  the  writer  would  regard  the  reac- 
tion as  holding  for  the  physiological  state.  But  this  positive  demon- 
stration has  not  yet  been  made.  The  theory  of  reversion  is  attractive; 
but  it  must  not  be  used  to  force  the  interpretation  of  an  experimental 
result.     The  high  glucose :  nitrogen  ratios  that  have  been  reported  in 


356  THE  FAT  METABOLISM 

occasional  cases  of  diabetes  have  not  been  so  controlled  as  to  exclude 
all  sources  of  error.  About  such  an  experiment,  involving  so  much  for 
the  theory  of  metabolism,  nothing  but  the  most  rigid  controls  can  be 
tolerated;  these  have,  to  date,  not  been  applied. 

The  Formation  of  Fat  from  Protein. — The  question  of  the  formation 
of  fat  from  protein  has  been  one  of  the  stock  problems  of  pathology 
and  to  some  extent  of  physiology.  For  physiology,  it  was  recognized 
that  the  solution  depended  upon  the  determination  of  the  formation 
of  sugar  from  protein.  Could  sugar  be  formed  from  protein,  then  there 
could  be  no  further  question  of  the  formation  of  fat  from  protein, 
since  fat  is  formed  from  sugar,  however  derived.  For  physiology, 
therefore,  the  demonstration  of  the  formation  of  sugar  from  amino- 
acids  carried  with  it  the  conclusion  that  a  living  organism  could  form 
fat  from  the  amino-acids  of  protein  via  sugar.  The  question  of  the 
formation  of  fat  from  protein  was  to  pathology,  however,  an  entirely 
different  matter;  and  widespread  misconception  of  the  actual  problem 
at  issue  has  resulted  in  an  enormous  volume  of  misdirected  research. 
The  proposition  of  the  formation  of  fat  from  protein,  as  contained  in 
the  usual  definition  of  fatty  degeneration,  ran  to  the  effect  that  in  the 
degenerated  cell  the  protein  of  the  protoplasm  was  converted  into  fat 
in  situ.  It  is  plain  that  the  demonstration  of  the  formation  of  fat 
from  sugar  derived  from  protein  in  an  organism,  in  nowise  supports 
the  thesis  that  in  a  diseased  cell  the  protein  of  the  protoplasm  is  con- 
verted into  fat.  Yet  this  misconception  pervades  most  of  the  writings 
of  pathologists.  The  data  are  now  in  hand  for  definite  decision  of  the 
question  of  the  origin  of  the  fat  in  degenerated  cells;  and  the  facts 
teach  us  that  this  fat  is  not  formed  from  the  protein  of  the  protoplasm 
of  the  same  degenerated  cells. 

It  must,  in  the  first  place,  be  realized  that  one  of  the  experiments 
long  interpreted  to  support  the  origin  of  fat  from  protein  in  the  sense 
of  the  pathologist,  is  actually  irrevalent  to  the  question  at  issue.  The 
eggs  of  the  fly  contain  little  fat;  blood  serum  contains  little  fat.  If 
the  eggs  of  the  fly  be  hatched  out  upon  blood  serum  and  the  larvae 
developed  thereon,  the  bodies  of  these  larvse  will  on  analysis  be  found 
to  contain  fat  in  excess  of  the  fat  of  the  eggs  and  of  the  food.  This 
simply  proves  that  the  organism  of  the  larvse  can  form  sugar  from 
protein  and  fat  from  this  sugar.  It  in  nowise  indicates  that  a  degenerat- 
ing cell  converts  the  protein  of  its  protoplasm  into  fat. 

Equally  important  is  it  to  realize  that  the  fatty  appearance  of 
degenerated  cells  need  not  mean  fat-content  in  the  chemical  sense. 
In  many  extreme  fatty  degenerations  of  the  cells  of  certain  organs, 
fat  is  not  present  in  amount  greater  than  in  the  normal  organs.  The 
histological  appearances  are  very  deceptive,  and  even  the  so-called 
specific  stains  for  fat  are  not  to  be  relied  upon  for  quantitative  inter- 
pretations. Fat  is  present  in  normal  cells  in  two  states:  free,  or  at 
least  so  loosely  combined  as  to  be  made  visible  by  fat  stains;  and  com- 
bined in  the  protoplasm,  in  such  state  that  fat  stains  do  not  react  with 


THE  CATAB0L1SM  OF  FAT  357 

it.  In  general  the  fat  that  stains  is  extractable ;  the  fat  that  is  combined 
and  will  not  stain  is  not  extractable.  If  the  tissue  be  digested  with 
trypsin,  this  combined  fat  is  set  free,  it  becomes  demonstrable  by 
stains  and  is  extractable.  In  a  fatty  degeneration,  autolytic  processes 
that  resemble  tryptic  digestion  split  the  fat-protein  combination  and 
render  the  fat  stainable.  It  is,  therefore,  clear  that  the  mere  presence 
of  more  stained  fat  may  be  simply  the  expression  of  the  setting  free 
of  fat  that  was  in  the  normal  cell  not  stainable  because  in  complex 
combination.  Apart  from  this  fat,  however,  it  may  be  shown  that 
all  the  fat  contained  in  degenerated  cells  is  deposited  from  the  outside. 

Three  lines  of  investigation  have  made  the  facts  and  relations  clear. 
If  a  starving  animal  (frogs  are  best,  though  small  animals  and  birds 
may  be  used)  be  subjected  to  an  intoxication  that  leads  to  marked 
fatty  degeneration,  as  phosphorus  poisoning,  it  will  be  found  that 
the  total  fat  of  the  body  is  not  increased.  It  is  either  not  affected  at 
all,  or  it  is  reduced  to  a  slight  extent,  as  might  be  expected  since  no 
food  is  ingested  for  the  support  of  the  metabolism.  Obviously,  there 
could  have  been  no  formation  of  fat  unless  this  was  covered  by  a  greater 
fat  catabolism.    This,  in  the  frog,  can  be  shown  not  to  have  occurred. 

If  the  different  organs  of  such  an  animal,  poisoned  with  phosphorus 
while  starving,  be  subjected  to  quantitative  analyses  for  fat,  it  will 
be  found  that  the  increases  in  the  fat  of  certain  degenerated  organs, 
especially  the  liver,  is  covered  by  the  lessened  fat-content  of  the  rest 
of  the  body.  In  other  words,  the  liver  has  been  filled  with  fat  drawn 
from  the  other  tissues;  the  process  has  been  one  of  fat  migration  and 
infiltration. 

Finally,  if  foreign  fats  be  used  in  the  experiment,  it  may  be  shown 
that  these  are  heaped  up  in  the  degenerated  organs.  If  a  starved 
dog  be  fattened  with  mutton,  it  will  be  found  that  apart  from  a  small 
amount  of  dog  fat  formed  from  the  sugar  derived  from  the  protein 
catabolism,  the  fat  of  the  dog's  body  is  mutton  fat  and  not  dog  fat.  If 
such  a  "  mutton  dog,"  as  they  are  called  in  the  laboratory,  be  poisoned 
with  phosphorus,  the  fat  in  the  fatty  degenerated  liver  will  be  found 
to  be  mutton  fat,  not  dog  fat.  Obviously,  the  accumulation  of  fat  in 
the  degenerated  liver  is  due  to  deposition  of  mutton  fat  from  the  fat 
depots  of  the  body,  and  not  to  the  formation  of  fat  from  protein  in  the 
protoplasm  of  the  liver  cells.  The  same  result  may  be  attained  by 
feeding  cream  to  a  cat  with  cantharides  nephritis;  butter  fat  will  be 
packed  into  the  diseased  renal  cells.  Other  foreign  fats  may  be 
employed  and  the  identical  result  secured. 

One  further  fact  makes  easier  the  application  of  these  considera- 
tions to  diseased  organs.  The  liver  is  of  all  organs  in  the  body  of  higher 
animals,  the  one  most  subject  to  fatty  infiltration;  infiltration  with 
fat  and  glycogen  are  indeed  to  be  regarded  as  functional  in  the  liver. 
Now  it  is  precisely  in  degenerations  of  the  liver  that  excesses  of  fat 
over  the  normal  are  to  be  found.  In  degenerations  of  the  kidneys, 
the  amount  of  fat  present  is  usually  not  in  excess  of  the  normal.    The 


358 


THE  FAT  METABOLISM 


liver  is  physiologically  a  fat  depot.  When  diseased  and  degenerated, 
it  remains,  or  indeed  becomes  still  more,  a  fat  depot.  Apparently,  the 
very  degeneration  of  the  hepatic  cells  limits  its  powers  of  control  over 
the  fatty  depositions,  makes  it  more  passive,  less  able  to  throw  off 
or  utilize  the  deposited  fat. 

It  is,  therefore,  certain  that  the  difference  between  fatty  infiltration 
and  fatty  degeneration  lies  in  the  normality  or  abnormality  of  the 
protoplasm;  it  does  not  lie  in  the  fat-content  or  in  the  postulated  forma- 
tion of  fat  from  the  diseased  protoplasm.  A  cell  with  fatty  infiltra- 
tion is  a  healthy  cell  containing  an  excess  of  fat  deposited  from  the 
outside.  A  cell  with  fatty  degeneration  is  a  diseased  cell  (whose  fat- 
protein  complex  in  the  protoplasm  has  been  in  whole  or  part  split), 
containing  an  excess  of  fat  deposited  from  the  outside.  The  difference 
lies  in  the  normality  or  abnormality  of  the  protoplasm  and  nucleus, 
not  in  the  amount  of  fat  and  most  certainly  not  in  the  derivation  of 
the  fat,  which  comes  from  the  fat  stores  of  the  body  and  is  not  derived 
by  synthesis  from  the  protein  of  the  protoplasm  of  the  cell  involved. 

Scheme  of  fat  metabolism. 


Hydrolysis 


Fat  in  diet 


Neutral  fat- 


(Protein-fat 
1  Phosphatids 
]  Sterins 
[Sebaceous  lipoids 

s. 

(Fatty  acids 

\     glycerol 


Glucose 


C02 

H20 

Butyric  acid 

i 
Beta-oxy-butyric  acid 

Aceto-acetic  acid  — >  Acetone 

1 
Acetic  acid 


Formic  acid     CO2   H2O 


H20  C02 


THE   PATHOLOGY    OF    FAT   METABOLISM 


So  far  as  known  there  are  but  two  pathological  deflections  in  the 
metabolism  of  fat.  The  first  lies  in  the  failure  of  the  diabetic  body 
to  form  fat  from  glucose  as  in  the  normal,  which  condition  was  dis- 
cussed under  diabetics.  The  second  lies  in  what  may  perhaps  best  be 
termed  acidosis  or  the  acetone  complex.  Under  this  term  we  include 
the  anomaly  wherein  fats,  instead  of  being  burned  completely,  are  in 
part  eliminated  as  acetone,  aceto-acetic  and  beta-oxy-butyric  acids. 

The  careful  investigations  of  the  past  decade  have  made  three  points 
clear  in  relation  to  this  subject,  (a)  The  acetone  bodies  are  not  derived 
from  carbohydrate  at  all.     (b)  The  acetone  bodies  may  be  derived 


THE  PATHOLOGY  OF  FAT  METABOLISM  359 

from  butyric  acid  and  also  from  several  amino-acids,  the  products  of 
protein  catabolism;  in  short  the  acetone  bodies  may  be  derived  from 
either  fat  or  protein,  (c)  In  the  amounts  and  under  the  circumstances 
under  which  the  complex  occurs  as  a  pathological  variation,  the  acetone 
bodies  must  have  been  derived  from  fat  and  not  from  protein. 

It  will  perhaps  be  best  first  to  discuss  the  origination  of  these  bodies 
from  protein.  The  foundation  for  this  derivation  rests  upon  an  experi- 
mental basis.  When  different  amino-acids  are  mixed  with  the  blood 
in  perfusion  experiments  with  the  dog's  liver,  some  are  noted  to  lead 
to  the  formation  of  acetone,  others  do  not.  All  the  amino-acids  have 
not  been  tested,  but  there  is  evidence  that  from  the  following  acetone 
may  be  formed:  leucin,  alanin,  phenylalanin,  tyrosin,  histidin,  and 
aspartic  acid.  The  probable  reactions  whereby  acetone  is  formed 
from  these  products  of  the  catabolism  of  protein  follow. 

Leucin  is  an  amino-isobutyl-acetic  acid.  The  reactions  through 
which  it  must  pass  to  reach  the  acetone  group  are  several: 

Leucin  ff-oxy-isobutyl-acetic  acid  Isovalerianic  acid 

CH3  CH3  CH3   CH3  CH3  CH3 


CH  CH 

I  i  I 

CH2  +  H20     ->  CH2  +  02    ->  CH2 

CHNH2  CHOH  COOH 

COOH  COOH  C02  H20 


From  this  point,  two  possibilities  are  open.  Either  the  isovalerianic 
acid  is  oxidized  at  the  beta  carbon,  and  the  two  lower  carbons  split 
oft'  as  C02  and  H20;  or  by  substitution  of  the  one  methyl  group  by  an 
hydroxyl  group  beta-oxybutyric  acid  would  be  formed. 

Isovalerianic  acid  Acetone  Isovalerianic  acid       /3-oxy-butyric  acid 

CH3  CH3  CH3  CH3  CH3  CH3  CH3 


v  v 

CH  CO                         CH                     CHOH 

I           +0     ->  or             I  -*          I 

CH2  CH2                     CH2 

2C02  2H20 

COOH  COOH                COOH 

Alanin,  phenylalanin,  and  histidin  are  all  derivatives  of  propionic 
acid.  Now  lactic  or  propionic  acid  cannot  be  converted  directly  into 
beta-oxy-butyric  acid.  Since  the  stated  experiment,  however,  indicates 
that  acetone  is  formed  from  them,  some  indirect  route  must  be  sought. 
The  argument  here  concerns  alanin  alone,  since  what  will  hold  for  it 
need  not  hold  for  the  two  aromatic  derivatives,  for  it  is  known  that 
when  the  benzol  ring  is  split  in  the  body,  the  fatty  acid  to  which  it 
was  attached  need  not  follow  the  normal  course  of  oxidation.  What 
holds  for  alanin  ought,  however,  to  hold  for  the  nearly  related  serin. 
The  relations  between  alanin  and  acetone  are  seen  in  the  equations: 


360 


THE  FAT  METABOLISM 


CH, 

CH(NH2) 
COOH 


CH, 

Ao 

CH, 


The  intermediary  stages  are  unknown. 

For  phenylalanin,  tyrosin,  and  histidin  it  is  probable  that  the  trans- 
formation follows  another  course,  it  having  been  made  quite  certain 
that  when  these  substances  are  converted  into  aceto-acetic  acid,  the 
four  carbons  of  the  acid  are  derived  two  from  the  propionic  group 
and  two  from  the  nucleus,  the  aromatic  ring  being  thereby  ruptured 
and  the  alpha  carbon  oxidized  to  the  carboxyl,  after  deaminization. 
The  following  illustration  will  elucidate  the  relations  in  the  molecules; 
tyrosin  is  not  illustrated  as  the  equation  practically  accords  with  that 
of  phenylalanin: 


Phenylalanin 

CH 


Aceto-acetic  acid 


Histidin 

N===CH 


H 


/ 


CH/ 


HC       / 

CH2 

CHNH2 

COOH 

Aspartic  acid  has  the  equation: 

COOH 

I 
CH(NH2) 


CH, 

Ao 

CH2 
COOH 


CHNH2 
COOH 


\U 


c 

I 

COOH 


CH, 

I 
CHOH 

CH2 

COOH 


By  reduction  of  the  upper  carboxyl  to  a  methyl  group  and  the  oxida- 
tion of  the  beta  carbon  after  deaminization,  beta-oxy-butyric  acid  would 
be  formed. 

Incidentally  remarked,  alanin,  aspartic  acid  and  leucin  are  being 
overworked.  For  these  are  among  the  very  ammo-acids  that  experi- 
mentally have  been  found  to  form  glucose.  For  diabetes  at  least, 
we  cannot  be  in  a  quandary  which  to  choose.  The  glucose  we  can 
scarcely  relate  to  any  other  factor  in  diabetes  than  to  the  amino-acids. 
And  in  the  quantities  in  which  sugar  and  the  acetone  bodies  respectively 
appear  in  the  diabetic,  contrasted  with  the  total  protein  catabolism, 


THE  PATHOLOGY  OF  FAT  METABOLISM  361 

we  have  no  alternative  than  to  relate  the  sugar  to  the  amino-acids 
and  the  acetone  bodies  to  the  fats. 

Furthermore,  it  has  been  suggested  that  beyond  the  stage  of  the 
amino-acids,  the  beta-oxy butyric  acid  might  be  formed  from  ammonium 
aldehyds.  Thus,  when  the  liver  is  perfused  with  acetaldehyd  ammonia, 
acetone  is  formed.  This  is  probably  accomplished  through  the  inter- 
mediary stage  of  aldol. 


CH3 
COH 

+ 

CH3 
COH 

CH3 

CH3 

=       CHOH      - 

• 

->      CHOH 
CH2 
COOH 

CH2 
COH 

We  are  not,  however,  aware  that  aldehyd  ammonia  is  formed  in  the 
body  in  the  manner  predicated  in  this  hypothesis. 

Granted,  then,  that  for  the  diabetic  the  amounts  of  acetone  bodies 
often  present  are  by  their  very  quantitive  relations  precluded  from 
derivation  from  the  protein  and  must  be  referred  to  the  fats,  are  there 
facts  known  for  the  non-diabetic  instances  of  the  acetone  complex 
that  suggest  that  in  them  the  bodies  in  question  are  derived  from 
protein  and  not  from  fat?  So  far  as  the  writer  is  aware,  all  the  facts 
speak  to  the  contrary;  they  plead  in  all  forms  of  acetone  acidosis  for 
the  derivation  of  the  ketonic  bodies  from  the  fats.  Whether  this,  how- 
ever, is  true  of  the  normal  trace  of  acetone,  may  be  possibly  questioned. 
In  the  equations  given  on  pp.  353  and  354  to  illustrate  the  combustion 
of  butyric  acid,  in  the  one  scheme  the  processes  of  oxidation  were 
carried  from  beta-oxy-butyric  through  aceto-acetic  acid  to  acetic 
acid;  in  the  other  illustration  the  process  was  carried  from  beta-oxy- 
butyric  acid  directly  to  acetic  acid.  According  to  the  first  scheme, 
acetone  in  traces  would  be  regarded  as  a  normal  product  of  the  com- 
bustion of  fat,  a  side  reaction.  According  to  the  second  scheme,  acetone 
would  not  be  formed  at  all  in  the  normal  combustion  of  fat.  If  now 
we  could  relate  to  the  protein  catabolism  the  normal  trace  of  acetone 
in  the  urine,  we  could  regard  the  second  scheme  as  representing  the 
course  of  the  burning  of  butyric  acid.  This  being  assumed,  we  could 
then  lay  our  finger  upon  the  point  of  failure,  the  defect  in  the  burning 
of  fat  that  in  the  clinical  instances  of  acetone  complex  leads  to  the 
formation  of  these  bodies  in  excess.  Special  reference  will  be  made 
to  this  after  we  have  considered  the  different  types  of  ketonuria,  under 
which  term  we  include  the  elimination  of  the  three  acetone  bodies — 
beta-oxy-butyric  and  aceto-acetic  acid,  and  acetone. 

Interesting  relations  exist  between  these  three  bodies.  The  faculty 
of  reduction  of  aceto-acetic  acid  to  acetone  is  very  limited,  and  there- 
fore no  mass  relation  holds  between  aceto-acetic  acid  and  acetone. 
Between  beta-oxy-butyric  acid  and  aceto-acetic  acid,  however,  an 
equilibrium  seems  to  exist.     The  administration  of  one  to  the  subject 


362  THE  FAT  METABOLISM 

of  acidosis,  results  also  in  increase  in  the  other;  it  makes  no  difference 
which  one  is  administered.  The  addition  of  either  one  to  liver  pulp 
results  in  the  appearance  of  the  other.  Clearly,  therefore,  where  the 
aceto-acetic  acid  is  not  removed  by  oxidation  or  conversion  into 
acetone,  we  have  the  relation :  beta-oxy-butyric  <  =  >  aceto-acetic 
acid.  For  practical  purposes,  therefore,  a  test  for  one  of  these  bodies 
is  a  test  for  both. 

The  urinary  acetone  complex  is  observed  under  widely  varying 
circumstances.    Definite  are  the  following  types: 

Diabetes. — This  is  perhaps  the  most  common,  as  it  is  also  the  most 
important.  It  has  been  discussed  under  diabetes.  Acidosis  occurs 
typically  in  phloridzin  intoxication. 

Starvation. — Here  we  have  one  of  the  best-studied  instances  of 
ketonuria.  A  few  days  after  food  is  withdrawn,  acetone  appears  in 
the  breath  and  urine.  Within  a  few  days,  aceto-acetic  acid  appears, 
to  be  soon  followed  by  beta-oxy-butyric  acid.  The  amounts  vary 
widely  with  different  individuals,  from  a  few  grams  to  50  per  day. 
The  higher  the  output,  the  more  marked  the  elimination  of  the  acids 
as  compared  with  the  acetone.  In  some  starving  subjects  eliminations 
are  met  with  quite  as  large  as  in  severe  diabetes.  With  the  persistence 
of  the  starvation,  the  acidosis  may  maintain  its  full  individual  range. 
The  administration  of  100  grams  of  sugar  will  be  followed  by  a  pro- 
nounced drop  in  the  acidosis.  Indeed,  by  the  daily  administration 
of  this  amount  of  sugar  to  an  otherwise  starving  subject  the  acetone 
complex  will  be  inhibited,  while  at  the  same  time  the  losses  of  flesh 
and  of  fat  continue,  since  100  grams  of  sugar  is  but  a  small  fraction 
of  the  fuel  requirements  of  the  body.  This  is  the  most  striking  of  the 
experiments  indicating  the  relationship  of  sugar  to  the  acetone  complex; 
it  is  not  starvation,  but  sugar-starvation  that  causes  the  acidosis. 
The  experiment  can  be  performed  in  another  way,  by  withdrawing 
all  carbohydrate  and  giving  full  rations  of  fat  with  the  minimal  ration 
of  protein.  At  once  a  marked  acidosis  will  result.  Curiously  enough, 
however,  this  is  only  temporary;  after  a  time  the  body  becomes  accus- 
tomed to  the  diet  and  the  acetone  bodies  slowly  retreat  to  the  normal 
output.  In  conditions  of  subnutrition  due  to  poverty,  acidosis  is 
rarely  present;  this  is  due  to  the  fact  that  meats  and  fats  are  first 
sacrificed  and  carbohydrates,  the  cheapest  foods,  are  retained.  The 
occurrence  of  the  acetone  complex  may  often  be  of  warning  to  the 
physician;  thus,  in  the  treatment  of  a  case  of  obesity,  it  will,  so  to 
speak,  mark  a  line  of  caution;  and  in  the  long-continued  infections, 
it  will  serve  to  indicate  the  degree  of  tissue  starvation  and  suggest 
change  in  the  feeding.  Starvation  does  not  provoke  acidosis  in  her- 
bivora  as  markedly  as  in  man  and  dog. 

Infectious  Diseases. — Many  infections,  especially  those  of  the  ali- 
mentary tract,  diphtheria  and  streptococcus,  present  a  marked  acidosis. 
It  is  not  parallel  to  the  fever,  but  rather  to  the  intensity  of  the  intoxica- 
tion, though  sometimes  high  acidosis  is  seen  in  mild  infections  and 


THE  PATHOLOGY  OF  FAT  METABOLISM  363 

little  acidosis  in  severe  infections.  The  administration  of  sugar  may 
result  in  a  diminution.  But  in  many  cases  the  diet  is  not  low  in 
carbohydrate  and  the  administration  of  sugar  has  no  effect.  Striking 
reduction  in  the  acidosis  in  diphtheria  has  been  reported  following 
the  use  of  antitoxin.  Children,  in  general,  display  infectious  acetonuria 
to  a  more  marked  degree  than  do  adults. 

Gastro-intestinal  Disturbances. — In  children  especially,  gastro-intestinal 
disturbances,  often  of  sudden  onset,  provoke  a  moderate  or  even  pro- 
nounced acidosis.  Individuals  seem  subject  to  recurrent  attacks.  There 
are  clearly  two  groups  of  these  cases;  one,  in  which  some  indiscretion 
in  diet,  some  decomposed  foodstuff,  provokes  a  gastro-enteritis,  with 
acidosis  as  one  of  the  symptoms;  and  the  second,  in  which  the  acidosis 
and  the  gastro-intestinal  symptoms  appear  as  results  of  a  common  cause, 
not  in  the  diet.  The  cases  of  the  last  group  are  most  interesting.  The 
attacks  usually  occur  in  children.  They  are  liable  to  recur  at  more  or 
less  regular  periods;  in  one  case  with  the  details  of  which  the  writer 
is  acquainted,  from  four  to  six  attacks  occur  per  year.  The  attacks 
usually  begin  with  vomiting,  which  is  persistent.  At  the  first  examina- 
tion of  urine,  acidosis  is  present.  The  recurrent  vomiting  lasts  for  two 
or  three  days,  and  then  gradually  quiets.  The  acidosis  ceases,  for  the 
most  part,  as  soon  as  the  paroxysmal  stage  is  passed.  As  a  matter  of 
close  observation  it  is  known  that  the  child  eats  well  of  all  food  and 
especially  including  carbohydrates  up  to  the  sudden  onset.  The 
administration  of  sugar  has  no  effect  upon  the  attacks,  though  the 
test  is  worth  little  on  account  of  the  persistent  vomiting.  Glucosuria 
is  not  present.  The  use  of  large  doses  of  sugar  as  soon  as  the  stomach 
will  tolerate  food,  has  no  effect  in  cutting  short  the  attack,  which 
always  ends  by  lysis.  Excessive  dieting  with  sugar  between  attacks 
has  no  influence  upon  the  occurrence  of  the  same.  There  is  undoubtedly 
something  sui  generis  in  these  attacks.  Similar  severity  of  vomiting 
in  pregnancy,  hysteria,  migraine,  etc.,  lead  to  no  such  acidosis  as  is 
seen  in  these  cases.  The  tendency  to  convulsive  seizures  and  to  coma 
is  also  a  feature  indicating  their  peculiar  nature.  In  sucklings  with 
enterocolitis  acetonuria  is  common,  and  here  it  is  the  result  of  carbo- 
hydrate subnutrition;  but  here  the  peculiar  features  of  the  attacks 
of  periodic  recurrent  vomiting  are  lacking.  In  carcinoma  of  the  stomach 
associated  with  pyloric  obstruction,  or  in  any  case  of  pyloric  obstruc- 
tion, the  subject  may  present  an  acetonuria  due  to  carbohydrate 
starvation,  the  result  of  the  loss  of  the  ingested  carbohydrates  through 
fermentation  in  the  stagnated  stomach. 

Eclampsia. — In  some  of  the  reported  cases  of  eclampsia  acidosis 
has  been  recorded.  Since  it  does  not  occur  in  all  cases,  it  cannot  be  held 
to  have  any  causative  association.  It  might,  however,  be  suggested 
that  in  the  eclamptic  woman,  the  occurrence  of  acidosis  as  a  result  of 
carbohydrate  insufficiency  might  be  the  incidental  cause  of  the  onset 
of  convulsions. 


364  THE  FAT  METABOLISM 

Phosphorus  Poisoning. — Acetonuria  is  to  be  observed  early  in  the 
course  of  phosphorus  poisoning.  It  remains  a  fixed  feature  in  the 
condition,  and  is  not  modified  by  the  ingestion  of  carbohydrates,  of 
which  it  is  obviously  independent,  since  it  occurs  before  the  body  can 
have  become  poor  in  glycogen. 

Narcosis. — The  postoperative  acidosis  of  anesthesia  is  now  well 
known.  Uncommon,  it  is  to  be  seen  much  more  often  with  the  use  of 
chloroform  than  following  the  use  of  ether.  There  are  three  groups  of 
cases.  In  the  first  group  is  found  only  the  presence  of  acetone  bodies 
in  the  urine.  This  does  not  occur  nearly  as  often  as  is  commonly 
stated;  the  exaggeration  is  due  to  the  fact  that  crude  tests  for  acetone 
have  been  usually  employed.  The  iodoform  test  is  often  found  posi- 
tive in  the  urine  when  the  keton  test  is  negative,  though  what  the 
substance  may  be  that  provokes  the  formation  of  iodoform  from  iodin 
is  not  known.  In  the  second  group  of  cases,  few  in  number  and  most 
often  seen  in  children,  the  urinary  findings  are  associated  with  moderate 
symptoms,  nausea,  vomiting,  headache  or  somnolence,  passing  off 
within  a  few  days.  The  conditions  in  the  third  group  of  cases  are 
serious  in  the  extreme.  There  is  heavy  acidosis,  often  convulsions, 
coma,  rapidly  developing  jaundice,  low  temperature  or  high  fever,  and 
death  in  the  larger  proportion  of  cases  in  from  three  to  five  days.  At 
postmortem  a  profound  degeneration  of  the  liver  is  found,  a  chloro- 
form necrosis  in  many  ways  comparable  to  phosphorous  necrosis. 
The  urine  contains,  in  addition  to  the  acetone  bodies,  ammonium 
lactate  and  various  amino-acids,  the  products  of  the  autolysis  of  the 
liver.  Here  also  the  condition  is  not  one  associated  with  the  carbo- 
hydrate metabolism,  it  is  a  result  of  the  necrosis  of  the  liver.  There 
is  no  glucosuria,  and  no  evidence  that  the  body  does  not  burn  sugar. 

In  many  other  conditions  occasional  instances  of  acidosis  are  en- 
countered. These  are  incidental  and  may  reasonably  be  attributed 
to  reduction  in  the  carbohydrate  metabolism. 

The  current  theory  of  acidosis  is  that  the  failure  in  the  combustion 
of  fat  is  secondary  to  failure  in  the  combustion  of  glucose,  either  because 
there  is  no  glucose  to  burn  or  because  the  body  has  lost  the  power 
of  burning  glucose.  This  is  expressed  in  the  statement  that  fat  can 
only  burn  in  the  fire  of  glucose.  Just  as  crude  oil  will  not  burn  alone 
but  will  burn  in  a  spray  of  steam,  so  fat  is  held  to  burn  only  when 
glucose  is  also  burned.  From  this  point  of  view  it  is  apparent  that 
in  every  instance  of  acetonuria  the  combustion  of  glucose  must  be 
faulty;  in  every  case  where  the  combustion  of  glucose  is  faulty,  one 
must  expect  an  acidosis.  Whenever  the  combustion  of  glucose  is 
normal,  the  combustion  of  fat  should  be  normal;  and  whenever  the 
combustion  of  fat  is  normal,  the  combustion  of  glucose  must  be  normal. 
These  statements  represent  the  current  doctrine.  The  writer  cannot 
share  this  exclusive  view.  Opposed  to  this  view  are,  firstly,  clinical 
and  experimental  facts;  and,  secondly,  theoretical  considerations. 

To  the  rules  as  above  asserted,  many  exceptions  exist,  and  these 


THE  PATHOLOGY  OF  FAT  METABOLISM  365 

exceptions  are  in  many  instances  of  crucial  meaning.  It  is  true,  as  a 
rule,  that  when  the  normal  body  is  fed  on  fat  and  meat  alone,  acidosis 
results.  But  why  should  it  occur  when  protein  is  abundant  ?  Instances 
have  been  reported  in  which  acidosis  occurred  with  a  diet  of  250  grams 
each  of  fat  and  meat;  such  an  amount  of  protein  will  yield  over  100 
grams  of  sugar.  Perhaps  it  may  be  urged  that  such  an  amount  of 
sugar  is  not  enough  to  assure  the  complete  combustion  of  so  much 
fat ;  but  this  rejoinder  at  once  makes  admission  of  the  existence  of  other 
factors  that  determine  the  combustion  of  fat.  And  in  direct  experi- 
ments, 100  grams  of  glucose  will  usually  exhibit  the  maximum  anti- 
ketonic  action.  This  lack  of  relationship  between  the  amount  of 
glucose  and  the  extent  of  combustion  of  fat  is  difficult  to  understand. 
A  small  amount  of  glucose  may  check  a  heavy  acidosis;  a  large  amount 
of  glucose  may  have  little  effect  upon  a  mild  acidosis. 

The  administration  of  sugar  has  little  or  no  effect  in  many  of  the 
cases  of  acidosis  in  connection  with  bacterial  infectious  diseases.  The 
action  of  diphtheria  antitoxin  in  reducing  the  acidosis  is  surely  striking 
enough.  Can  anyone  believe  that  the  diphtheria  poison  depresses  the 
combustion  of  glucose  (no  sign  of  which  is  to  be  noted),  and  through 
it  the  burning  of  the  fat;  and  when  the  inhibition  of  the  combustion 
of  glucose  is  raised  by  the  antitoxin,  the  combustion  of  fat  is  only 
secondarily  relieved?  In  severe  cases  of  diabetes,  the  administration 
of  increased  protein  or  of  sugar  may  increase  the  acidosis  instead  of 
lessening  it.  It  may  be  replied  that  in  these  cases  the  ingested  sugar 
does  not  burn;  but  why  should  its  mere  presence  still  further  reduce 
the  combustion  of  fat?  There  are  cases  of  diabetes  with  good  tolera- 
tion for  carbohydrate  who  display  for  months  high  acidosis,  the  course 
of  which  is  quite  independent  of  the  carbohydrate  of  the  diet  or  the 
glucosuria.  On  the  other  hand,  there  are  cases  of  diabetes  with  low 
toleration  for  carbohydrate  who  present  little  or  no  acidosis.  Such 
cases  recall  the  gradual  disappearance  of  the  acidosis  in  normal  indi- 
viduals who  are  living  on  fat  and  protein;  at  first  the  acidosis  is  marked, 
then  it  gradually  disappears.  To  offer  as  explanation  for  these  cases, 
that  the  body  has  learned  to  burn  fat  without  sugar  is  surely  a  lame 
procedure.  To  continue  the  use  of  such  language,  one  might  say  that 
some  diabetics  who  have  good  powers  of  burning  sugar  have  forgotten 
how  to  burn  fat  with  it.  The  plain  fact  in  diabetes  is  that  any  factor 
that  aids  in  the  normal  course  of  metabolism  (including,  of  course,  the 
burning  of  sugar),  any  factor  that  increases  the  health  of  the  body  in 
any  way,  tends  to  aid  in  the  proper  combustion  of  fat,  and  vice  versa. 
That  is  the  reason  why  alcohol,  while  sparing  the  sugar  and  fat  com- 
bustions, nevertheless  actually  lowers  the  utilization  of  each.  Finally, 
the  acidosis  of  idiopathic,  recurrent  vomiting  in  children,  and  that 
resulting  from  poisoning  with  phosphorus  and  chloroform  is  certainly 
not  dependent  upon  the  combustion  of  sugar.  These  attacks  strike 
in  the  midst  of  a  normal  metabolism.  There  are  no  indications  of  any 
defect  in  the  carbohydrate  metabolism,  there  is  no  glucosuria.     It  is 


366  THE  FAT  METABOLISM 

not  possible  to  believe  that  any  conditions,  outside  of  excessive  exercise 
and  refrigeration,  could  free  the  body  of  glycogen  within  the  short  time, 
often  only  a  few  hours,  in  which  these  forms  of  acidosis  develop.  We 
know  now  what  is  required  to  free  the  body  of  storage  glycogen.  In 
many  of  these  cases,  moreover,  the  subjects  are  ingesting  carbohydrate. 
In  such  cases  the  contention  that  sugar  is  not  being  burned  can  be 
demonstrated  in  only  one  way — by  the  determination  of  the  respiratory 
quotient.  There  is  not,  to  the  knowledge  of  the  writer,  one  such  deter- 
mination on  record.  It  is  possible  that  a  body  might  consume  sugar 
and  yet  not  burn  it  and  not  eliminate  it.  But  for  such  a  situation  to 
be  demonstrated,  the  respiratory  quotient  is  indispensable. 

The  support  of  this  hypothesis  places  us  in  a  quandary  when  the 
facts  determined  for  the  metabolism  of  normal  individuals  on  a  protein- 
fat  regimen  are  considered.  Acidosis  appears  at  first  in  all  cases,  no 
matter  how  large  the  intake  of  protein.  An  amount  of  sugar  large 
enough  to  check  the  acidosis  in  starvation  or  to  modify  greatly  the 
acidosis  of  a  diabetic,  may  be  without  effect  when  derived  from  a 
heavy  ration  of  protein  in  the  subject  on  a  protein-fat  diet.  That  the 
body  spares  its  fat  and  burns  sugar  whenever  it  is  available  is  one  of 
the  best-known  laws  of  metabolism.  The  body  does  not  burn  its  fat 
until  the  glycogen  depots  of  the  body  are  depleted  and  the  sugar  of 
the  body  reduced  to  the  minimum;  but  then  when  it  needs  to  burn 
fat,  it  cannot,  according  to  this  hypothesis,  burn  it  properly  because  it 
has  not  the  sugar  to  burn  with  it.  When  now  sugar  is  given  indirectly 
in  the  form  of  protein,  the  body  is  still  unable  to  burn  the  fat  properly. 
If  time  be  given,  however,  the  body  adapts  itself  to  the  function  of 
burning  the  fat,  even  if  the  protein  ration  be  minimal.  Certainly  it 
is  not  possible  to  explain  this  train  of  facts  logically  and  satisfactorily 
on  the  hypothesis  that  the  body  burns  fat  only  in  the  fire  of  sugar. 

Theoretical  considerations  dealing  on  the  one  hand  with  the  equa- 
tions for  the  burning  of  sugar  and  fat,  and  on  the  other  hand,  with 
our  conceptions  of  fermentations,  are  sufficient  in  the  opinion  of  the 
writer  to  preclude  the  acceptance  of  the  hypothesis  that  fats  are  burned 
only  in  the  fire  of  sugar.  It  must  be  clearly  realized  that  inability 
to  explain  any  set  of  facts  imposes  no  obligation  to  accept  an  unsatis- 
factory hypothesis.  The  idea  that  an  hypothesis  is  like  a  poor  bridge, 
to  be  kept  and  used  until  a  new  structure  is  built,  is  unscientific;  where 
ignorance  exists  it  must  be  recognized.  That  many  of  the  facts  of  the 
relations  between  the  combustions  of  fat  and  glucose  are  apparently 
explained  by  the  hypothesis  under  consideration  is  true;  that  the 
facts  on  analysis  are  not  such  as  to  exclude  every  other  explanation 
is,  however,  equally  true.  Many  a  line  of  apparent  least  resistance 
has  been  found  to  lead  to  an  erroneous  conclusion.  When  one  contem- 
plates the  whole  scope  of  the  metabolisms  of  fat  and  sugar,  one  must 
assume  that  they  have  their  own  systems  of  enzymic  action.  In  the 
dog  (carnivorous  and  dependent  more  upon  fat  than  upon  sugar  for 
the  body  heat),  and  in  the  rabbit  (herbivorous  and  depending  largely 


THE  PATHOLOGY  OF  FAT  METABOLISM 


367 


upon  sugar  for  body  heat),  no  such  dependence  of  the  combustion  of 
the  fat  upon  that  of  sugar  exists  as  is  postulated  for  man.  Interactions 
occur  between  the  metabolisms,  and  failure  in  one  might  under  certain 
circumstances  entrain  failure  in  the  other;  but  that  a  fundamental 
metabolism  should  be  absolutely  dependent  upon  another  metabolism, 
that  a  defect  in  the  one  must  inevitably  result  in  inhibition  of  the 
other,  is  a  situation  so  at  variance  to  our  general  conceptions  of  metab- 
olism and  of  physiological  compensation  and  adaptation  as  to  be 
a  priori  very  doubtful. 

When  one  contemplates  the  reactions  whereby  butyric  acid  may 
be  burned,  one  is  still  more  at  loss  to  understand  why  the  combustion 
of  sugar  should  control  the  combustion  of  butyric  acid.  So  far  as  is 
known,  in  all  cases  of  acidosis,  the  molecule  of  higher  fatty  acid  is 
burned  normally  down  to  butyric  acid.  Disregarding  as  improbable 
the  direct  transformation  of  butyric  acid  to  propionic  acid  by  oxida- 
tion of  the  alpha  carbon,  there  are  two  possible  routes. 


Butyric 
acid 

CH3 
I 
CH2 

CH2 

I 
COOH 


b-oxy-butyric 
acid 

CH3 

I 
•      CHOH/ 

CH2 

I 
COOH 


Aceto-acetic 
acid  I 

CH3     / 

I         / 
CO    — 

/  I 

/   CH2 
I 
COOH 


Acetic  acid 

CH3 
OOH 

CH3 

I 
COOH 


Formic 
acid 


End 
products 

C02  H20 


CH3 
COOH 


HCOOH  -•  C02  H20 

C02  H20 

HCOOH  -+  C02  H20 


Formic  acid  End  products 

-*  C02  H20 

HCOOH        C02  H20 

C02  H20 

HCOOH   -♦  C02  H20 


The  side  reaction  from  aceto-acetic  acid  to  acetone  we  may  disregard, 
since  it  has  only  the  same  meaning  as  the  aceto-acetic  acid.  If  the 
lower  scheme  be  correct,  the  oxidation  of  the  beta  carbon  of  beta-oxy- 
butyric  acid  is  completed,  cleavage  occurs  between  the  «  and  /3,  and 


368  THE  FAT  METABOLISM 

two  molecules  of  acetic  acid  are  formed.  Aceto-acetic  acid  would, 
therefore,  be  regarded  as  an  abnormal  substance.  This  view  is  only 
tenable  if  we  assume  that  the  traces  of  acetone  present  in  normal 
urine  are  derived  from  the  alanin  group  of  amino-acids  of  the  protein 
catabolism.  In  the  opinion  of  the  writer,  the  first  scheme  is  the  better 
founded.  The  defect  in  acidosis  under  the  first  scheme,  lies  in  the  loss 
of  the  power  of  oxidizing  beta-oxy-butyric  acid  to  aceto-acetic  acid, 
and  of  oxidizing  aceto-acetic  acid  to  acetic  acid.  The  administration 
of  these  two  acids  in  conditions  of  acidosis  is  followed  by  their  elimina- 
tion unchanged.  If  one  accepts  the  second  scheme,  though  it  is  less 
probable,  the  defect  consists  in  the  fact  that  a  partial  oxidation  of 
beta-oxy-butyric  acid  to  aceto-acetic  acid  occurs  instead  of  immediate 
and  complete  oxidation  with  cleavage  between  the  alpha  and  beta 
carbons.  From  the  standpoint  of  the  modern  theories  of  oxidation, 
one  might  assume  that  the  aceto-acetic  acid  is  the  normal  intermediary 
suboxid  stage,  just  as  it  appears  in  the  oxidation  of  copper  in  alkaline 
solution : 

C11S04  +  2KOH  =  K2S04  +  Cu(OH)2 
Cu(OH)2  =  CuO  +  H20 

On  this  assumption,  we  would  infer  that  in  acidosis  something  had 
intervened  to  check  the  reaction  of  oxidation  at  the  intermediary 
stage,  just  as  the  oxidation  of  the  copper  can  be  checked  at  the  oxy- 
hydrate  stage.  However  one  regards  this,  one  is  unable  chemically  to 
understand  how  the  presence  of  glucose  in  the  system  or  the  simulta- 
neous combustion  of  glucose  would  have  the  power  to  make  or  mar 
this  oxidation.  Medical  writers  have  suggested  the  term  "secondary 
oxidation,"  apparently  unmindful  of  the  fact  that  coupled  reactions 
have  long  been  known.  That  the  presence  of  one  body  may  make 
possible  the  oxidation  of  another  body  is  well  understood.  A  good 
illustration  is  afforded  in  the  following  reaction: 

Chromic  acid  +  tartaric  acid  =  formic  and  other  acids  (very  slow  reaction) 
Chromic  acid  +  arsenous  acid  =  arsenic  acid  (very  rapid  reaction) 

Now  arsenous  acid  has  no  action  upon  tartaric  acid.  When,  however, 
the  two  systems  are  mixed,  the  rapid  oxidation  of  arsenous  to  arsenic 
acid  by  the  chromic  acid  is  accomplished  as  before,  while  at  the  same 
time  the  tartaric  acid  is  also  rapidly  oxidized.  The  assumption  of  a 
dependence  of  the  oxidation  of  butyric  acid  upon  the  oxidation  of 
glucose  violates,  therefore,  no  theoretical  requirement.  We  might 
suggest  some  such  scheme  as  the  following,  based  upon  the  assumption 
that  there  is  an  intermediary  stage  in  the  conversion  of  glucose  into 
lactic  acid,  and  that  it  is  this  intermediary  product  that  acts  as  the 
accelerating  agent  in  the  combustion  of  beta-oxy-butyric  acid. 

Glucose  — ►  pi  — ->  lactic  acid,  —>—>—>  —>  C02  and  H20 
beta-oxy-butyric  acid  +  pi  =  — >  — >  — >  C02  and  H20 


THE  PATHOLOGY  OF  FAT  METABOLISM  369 

Obviously,  inhibition  in  the  formation  of  pi  would  lead  to  cessation  in 
the  combustion  of  the  fatty  acid.  What  makes  it  difficult  of  accepta- 
tion is  the  fact  that  the  oxidation  of  butyric  acid  to  acetic  acid  can 
be  accomplished  by  bacteria,  by  colloidal  metals,  by  different  chemical 
operations  and  by  carnivora  and  herbivora  directly  and  in  the  absence 
of  glucose — but  not  by  man. 

Two  explanations  may  be  suggested  for  the  occurrence  of  acidosis. 
These  will  not  account  for  all  cases,  and  for  those  thus  inexplicable 
we  must  await  elucidation  through  research.  One  is  that  the  ferment 
of  the  reaction  is  lacking;  in  diabetes  the  lack  of  the  normal  ferment 
for  the  combustion  of  butyric  acid  goes  in  many  cases  hand  in  hand 
with  the  lack  of  the  pancreatic  zymo-excitor  for  the  combustion  of 
glucose.  The  second  explanation  is  that  when  the  entire  maintenance 
of  the  heat  of  the  body  is  thrown  upon  the  fat  metabolism  (suddenly 
or  through  a  too  prolonged  period  of  time),  the  overload  leads  to  a 
quantitative  incompleteness  in  the  reaction.  The  body  can  convert 
just  so  much  aceto-acetic  acid  into  acetone  and  no  more.  The  liver 
can  deaminize  just  so  much  ty rosin  and  no  more.  Possibly  a  body 
can  burn  just  so  much  butyric  acid,  and  when  the  function  is  taxed 
the  reaction  of  oxidation  is  incomplete.  To  use  a  common  term,  the 
acidosis  would  be  the  result  of  overwork.  It  is  not  alleged  that  these 
two  explanations  will  account  for  all  the  instances  of  acidosis;  but  they 
will  account  for  many.  And  while  the  failure  to  account  for  all  the 
instances  of  acidosis  in  nowise  discredits  these  explanations,  the  failure 
to  account  for  any  instance  of  acidosis  is  fatal  to  the  hypothesis  that 
all  ketonic  acidosis  is  due  to  defect  in  the  burning  of  sugar,  through 
which  alone  the  combustion  of  fat  is  assumed  to  be  possible. 


24 


CHAPTER   VI 

THE  METABOLISM  OF  PROTEIN 

Like  sugar  and  fat,  protein  bears  a  dual  role  in  the  body:  it  is  con- 
cerned with  growth  and  regeneration  of  tissues,  in  the  maintenance  of 
the  status  quo;  and  it  is  a  fuel.  In  the  case  of  sugar  and  fat,  though  the 
importance  of  the  anabolized  states  is  fundamental  to  cellular  structure, 
quantitatively  by  far  the  largest  portions  of  sugar  and  fat  used  in  the 
body  are  utilized  simply  as  fuel.  In  the  case  of  protein  the  converse 
is  true;  in  a  properly  regulated  diet  the  use  of  protein  as  fuel  is  minimal, 
its  utilization  is  most  largely  concerned  with  the  processes  of  cellular 
anabolism.  That  meat  can  be  used  as  the  sole  food  is  true.  It  contains 
enough  fat  and  sugar  (a  part  from  the  glucose  formed  from  it)  to  furnish 
the  fat  and  sugar  needed  in  the  lipoid-  and  sugar-carrying  complexes 
of  the  tissues;  and  it  can  serve  as  the  exclusive  fuel,  though  a  very 
wasteful  form  of  fuel.  It  is  a  general  rule  that  the  animal  body  does 
not  tolerate  ingestions  of  protein  in  excess  of  the  needs  of  its  anabolism : 
all  excess  is  not  stored  but  promptly  burned.  The  determination  of 
the  line  where  tissue  utilization  ends  and  fuel  utilization  begins,  or  in 
other  words,  to  separate  what  we  term  the  endogenous  and  the  exogenous 
catabolisms,  is  extremely  difficult;  and  misconception  of  this  relationship 
has  brought  much  confusion  into  the  subject. 

The  problem  of  the  state  of  resorption  of  the  products  of  the  digestion 
of  protein  resolves  itself  into  two  possibilities,  if  logic  and  the  known 
facts  are  alike  to  be v  respected.  Either  the  amino-acids  and  peptids 
are  resorbed  unchanged,  and  transported  to  the  tissues  in  that  state 
for  utilization  or  storage,  as  far  as  needed  by  the  cells;  or  blood  protein 
is  formed  in  the  intestinal  wall  by  synthesis,  and  the  blood  protein 
carried  to  the  cells  for  utilization.  To  attempt  to  occupy  a  middle 
ground,  that  only  so  much  protein  is  synthesized  in  the  intestine  as 
may  be  needed  in  the  tissues,  the  excess  of  amino-acids  deaminated 
there  and  the  products  carried  to  the  liver  to  be  converted  into  sugar 
and  urea,  is  only  to  confuse  the  situation.  To  inquire:  should  all  the 
amino-acids  be  built  back  into  protein  in  the  intestinal  wall  when 
only  a  fraction  thereof  will  be  needed  by  the  tissues? — does  not  hit 
the  mark.  How  should  the  intestinal  wall  know  how  much  synthesized 
protein  will  be  needed  by  the  tissues?  Either  there  is  total  synthesis 
(except  for  superfluous  amino-acids)  or  there  is  no  synthesis  in  the 
intestinal  wall.  To  the  writer,  sound  reasoning  favors  the  theory  of 
synthesis  of  protein  from  amino-acids  in  the  intestinal  wall.  The 
derivation  and  utilization  of  the  blood  proteins  is  incomprehensible 


THE  METABOLISM  OF  PROTEIN  371 

on  any  other  hypothesis.  Nor  can  one  understand  how  the  amino- 
acids,  if  absorbed  unchanged,  could  escape  deaminization  in  the  liver. 
It  is  true  that  under  the  theory  of  the  blood  proteins  as  the  common 
substrate  of  all  the  protein  anabolism  of  the  tissues,  intracellular  hydro- 
lytic  cleavages  must  precede  the  synthesis  of  special  proteins.  But 
under  these  circumstances  the  different  body  cells  have  offered  to  them 
all  the  assortment  of  amino-acids,  which  would  not  be  the  case  if  they 
were  dependent  upon  the  products  of  the  digestion  of  protein  of  each 
meal.  The  problem  of  the  definition  of  the  endogenous  and  exogenous 
protein  catabolism  is  identical  in  either  case;  in  the  one  case  the  excess 
of  amino-acids  is  catabolized;  in  the  other  case  the  excess  of  blood 
protein  is  catabolized,  the  concept  of  equilibrium  is  as  applicable  to 
one  as  to  the  other.  Without  further  discussion,  since  an  analytical 
investigation  of  the  question  is  not  yet  possible,  we  shall  found  our 
presentation  of  the  metabolism  of  protein  upon  the  assumption  that 
the  products  of  the  digestion  of  protein  are  in  the  intestinal  wall  con- 
verted into  the  stock  proteins  of  the  blood,  these  serving  as  the  substrate 
of  the  anabolism  of  the  special  protein. 

The  alternative  proposition  runs  to  the  effect  that  the  products  of 
the  digestion  of  protein  are  absorbed  unchanged  and  transported  to  the 
tissues,  largely  to  the  muscles,  and  there  stored.  Stored  they  must 
be,  since  the  processes  of  anabolism  cannot  be  supposed  to  follow  the 
habits  of  eating.  How  stored?  While  there  can  be  no  doubt  that 
the  tissues  and  muscles  can  store  amino-acids,  and  recent  investiga- 
tions seem  to  have  greatly  enlarged  our  conceptions  of  such  a  storage 
there,  to  the  writer  it  does  not  seem  biologically  or  chemically  logical 
to  regard  this  as  the  actual  state  of  affairs.  There  must  be  a  reaction 
of  formation  of  blood  protein;  the  constancy  of  the  blood  in  starvation, 
in  hibernation  and  in  the  anadromous  fishes  during  the  period  of 
sexual  migration,  and  the  apparent  dependence  of  the  various  body 
processes  on  the  stock  of  blood  protein,  make  this  assumption  neces- 
sary. Either  the  stock  proteins  of  the  blood  are  formed  in  the  intestinal 
wall,  or  they  are  formed  in  the  muscles.  The  fact  that  the  muscles 
do  build  down  protein  is  clear  in  starvation,  other  cells  of  the  body,  of 
course,  sharing  the  function.  That  they  should  store  large  stocks  of 
amino-acids  and  release  or  use  them  for  anabolic  processes  seems  to 
the  writer  far  less  likely  than  that  they  should  convert  these  amino- 
acids  into  the  stock  proteins  of  the  blood.  Against  the  idea  of  the 
transportation  of  the  amino-acids  to  the  peripheral  tissues,  apart 
from  considerations  of  the  toxicity  of  the  unchanged  products  of  the 
digestion  of  protein,  stands  the  general  proposition  that  specialization 
at  the  portal  of  entrance  affords  to  the  organism  not  only  greater  pro- 
tection against  deprivation  through  hepatic  combustion,  but  also  a 
wider  choice  and  scope  in  utilization  than  could  be  afforded  by  speciali- 
zation in  the  peripheral  tissues.  Future  researches  may  indicate  the 
contrary  of  this  interpretation,  and  in  any  event  it  is  proper  and  neces- 
sary to  vest  in  the  muscular  system  full  powers  for  the  synthesis  of 


372  THE  METABOLISM  OF  PROTEIN 

protein  from  amino-acids.  But  for  the  present  purposes  of  this  work, 
we  shall  accept  the  modus  operandi  as  stated,  and  consider  the  amino- 
acids  of  the  alimentary  tract  to  be  converted  into  the  stock  proteins 
of  the  blood  in  the  cells  of  the  intestinal  wall. 

The  state  of  resorption  of  the  products  of  protein  digestion  is  to  be 
regarded,  as  stated  in  the  closing  discussion  of  the  resorption  of  protein, 
as  peptids  and  amino-acids.  The  wide  leeway  that  is  necessary  to 
permit  the  synthetic  functions  to  form  serum  albumin  and  serum 
globulin  from  all  sorts  of  ingested  proteins,  makes  it  appear  certain 
that  the  digestion  of  proteins  is  continued  down  to  very  simple  peptids. 
These  peptids  and  amino-acids  are  on  resorption  assumed  to  be  con- 
verted into  serum  albumin  and  serum  globulin.  These  two  proteins  of 
the  blood  serum  are  to  be.  regarded  as  the  stock  proteins  of  the  body, 
they  are  carried  to  all  the  cells  and  tissues  and  are  the  original  stock 
or  basic  material  from  which  are  formed  all  the  special  proteins  in  the 
body.  These  stock  proteins  bear  the  biological  stamp,  which  is  another 
argument  in  favor  of  a  complete  or  nearly  complete  hydrolysis  of  the 
proteins  in  the  act  of  digestion. 

The  site  of  the  conversion  of  the  amino-acids  and  peptids  into  serum 
albumin  and  serum  globulin  is  primarily  the  epithelial  membrane  of 
the  intestine  (the  resorption  membrane).  We  assume  that  the  liver 
has  little  or  nothing  to  do  with  this  reaction  because  of  the  absence  of 
signs  indicating  a  flooding  of  the  tissues  with  amino-acids  when  the 
blood  from  the  intestines  is  switched  directly  into  the  venous  circula- 
tion. If  the  formation  of  -the  stock  proteins  of  the  blood  wTere  in  chief 
the  function  of  the  liver,  it  is  not  to  be  comprehended  how  the  estab- 
lishment of  the  Eck  fistula  is  followed  by  so  little  disturbance  in  metab- 
olism. It  may  be  proper,  however,  under  all  circumstances  to  accord 
to  the  liver  such  power  and  to  predicate  the  formation  there  of  the 
proteins  from  such  amino-acids  and  peptids  as  have  escaped  conversion 
in  the  wall  of  the  intestine.  But  the  chief  synthesis  (apart  from  the 
question  of  the  peripheral  tissues)  must  according  to  our  present  light 
be  located  in  the  wall  of  the  intestine — just  as  the  synthesis  of  neutral 
fat  from  fatty  acids  and  glycerol  must  be  located  in  the  wall  of  the 
intestine.  The  mechanism  of  the  synthesis  of  albumin  and  globulin 
from  the  amino-acids  and  peptids  we  rest  upon  the  action  of  an  enzyme. 
One  cannot  resist  the  hypothesis  of  the  so-called  reversed  action  of 
the  proteolytic  ferments.  But  special  factors  must  needs  be  operative 
here,  since  from  the  products  of  the  digestion  of  many  kinds  of  protein 
of  widely  varying  composition  and  construction,  the  intestinal  wall 
builds  serum  albumin  and  serum  globulin,  and  in  each  species  places 
upon  these  the  biological  stamp  of  the  species.  We  possess,  however, 
no  other  concept  than  that  of  enzyme  action  under  which  the  synthesis 
of  the  blood  proteins  becomes  at  all  comprehensible.  For  him  who 
is  fond  of  wearing  an  intellectual  veil,  the  notion  of  vital  action  will 
here  find  for  the  present  an  easy  application.  The  serum  albumin  and 
serum  globulin  of  the  blood  have  been  designated  as  the  stock  proteins. 


THE  ANABOLISM  OF  PROTEIN  373 

By  this  it  is  not  to  be  inferred  that  they  are  the  sole  proteins  present 
in  the  blood  plasma.  But  the  others  are  there  present  in  the  merest 
traces,  and  the  quantitative  relations  alone  compel  us  to  accord  to 
the  named  proteins  the  role  of  stock  proteins.  These  two  proteins 
present  very  different  physical  properties,  although  data  have  been 
advanced  tending  to  show  that  the  albumin  passes  into  the  globulin. 
This,  however,  is  made  improbable  by  the  fact  that  serum  globulin 
contains  glycocoll  in  goodly  amount,  while  serum  albumin  is  devoid 
of  glycocoll;  and  this  amino-acid,  it  will  be  recalled,  is' centrally  located 
in  a  peptone,  being  one  of  the  components  of  the  resistant  polypeptid. 
We  will,  therefore,  regard  them  as  distinct  proteins,  and  each  probably 
serves  distinct  purposes  in  the  syntheses  of  the  different  body  proteins. 
The  quantitative  relations  of  serum  albumin  and  serum  globulin  in 
the  blood  serum  are  fairly  constant  for  each  species;  the  difficulties  in 
separation  and  estimation  could  account  for  all  the  apparent  fluctuations 
in  the  ratio.  , 

These  stock  proteins  we  are  to  regard  as  the  materials  from  which 
all  the  special  proteins  of  the  body  are  formed.  They  are  also  the 
state  in  which  protein  is  burned  as  fuel.  We  possess  exhaustive  quantita- 
tive studies  on  the  protein  content  of  blood  serum  after  meals  rich  in 
protein.  We  may  assume  that  there  is  for  these  proteins  a  physio- 
logical limit,  just  as  there  is  a  limit  for  blood  sugar.  If  more  sugar 
be  poured  into  the  blood  than  is  needed,  it  is  converted  into  glycogen 
and  stored;  if  much  more  than  needed  be  poured  into  the  circulation, 
so  that  the  conversion  into  glycogen  cannot  hold  the  sugar  content 
down  to  the  maximum  normal  blood  limit,  glucosuria  occurs.  Now 
in  the  case  of  blood  proteins  there  is  no  storage  state,  nor  is  there  a 
physiological  albuminuria  whose  effect  is  simply  to  reduce  the  blood 
content  of  protein.  When  an  excess  of  protein,  beyond  the  needs  of 
the  body  tissues,  is  poured  into  the  blood,  the  increased  concentration 
results  in  increase  in  protein  catabolism,  and  the  excess  of  protein  is 
split,  deaminated,  burned  and  eliminated.  This  is  the  fraction  of  the 
protein  catabolism  that  we  term  exogenous,  meaning  by  this  that  the 
protein  has  never  been  incorporated  in  the  state  of  protoplasm,  but 
being  in  the  blood  in  excess,  is  catabolized.  In  a  certain  physiologi- 
cal sense  this  excess  of  protein  may  be  regarded  as  a  foreign  body, 
which  the  metabolism  disposes  of  by  hydrolysis,  deaminization,  oxida- 
tion, and  elimination. 


THE    ANABOLISM   OF   PROTEIN 

Under  the  term  anabolism  of  protein  we  understand  the  formation  of 
the  special  proteins  of  the  tissues  from  the  stock  proteins  of  the  blood ; 
and  also  the  formation  of  other  special  tissues  constituents,  such  as 
purin  and  pyrimidin.  The  special  proteins  must  be  formed  progres- 
sively during  the  growth  of  the  individual;  and  the  loss  by  cell  death 


374  THE  METABOLISM  OF  PROTEIN 

must  be  replaced  in  the  adult  body.  All  cells  have  a  limited  life,  they 
die  and  the  number  is  maintained  through  cell  regeneration;  in  the 
growth  of  the  new  cells  new  special  proteins  are  required,  since  the 
dead  cells  are  catabolized.  There  are  cells  that  are  lost  to  the  body 
though  not  catabolized.  The  spermatozoa,  the  horny  cells  of  the  skin 
and  the  desquamated  epithelia  of  the  mucous  membranes  are  lost  to 
the  body  though  not  catabolized,  just  as  are  the  proteins  of  the  hair 
and  nails.  The  sum  total  of  these  losses  is  small  in  comparison  with 
the  internal  destruction  of  cells,  seen  in  its  most  rapid  phases  in  the 
leukocytes  and  erythrocytes.  During  the  period  of  growth  and  during 
adult  years  the  synthesis  of  special  proteins  is,  therefore,  for  the  same 
purpose — the  equipment  of  new  cells. 

It  is,  however,  not  proper  to  limit  the  conception  of  the  anabolism 
of  protein  to  the  equipment  of  new  cells.  Cells  have  an  intracellular 
metabolism,  protoplasm  is  used  up  in  the  course  of  the  cellular  activities, 
and  there  must  be  a  regular  replacement  of  protoplasm  within  the  cell 
just  as  there  is  regular  replacement  of  cells  in  an  organism.  Bacteria 
have  a  metabolism  independent  of  reproduction,  and,  of  course,  to 
predicate  any  other  condition  would  violate  the  law  of  conservation 
of  energy.  It  is  possible  in  an  indirect  way  to  indicate  that  such  a 
intracellular  metabolism  exists.  Lymphatic  tissue  contains  about 
80  parts  of  protein  to  1  part  of  purin.  The  muscular  and  connective 
tissues  contain  less,  so  we  can  make  the  calculation  on  the  basis  of  at 
least  200  to  1.  Now  the  average  normal  endogenous  purin  output  is 
about  0.3  gram  per  day.  The  corresponding  figure  for  this  in  total 
nitrogen  output,  would  amount,  therefore,  to  60  grams  of  protein 
catabolized  per  day — which  is  higher  than  the  actual  figure.  This  may 
be  interpreted  to  indicate  that  there  is  an  intracellular  metabolism 
involving  nucleus  to  a  far  greater  extent  than  protoplasm,  since  were 
the  transformations  equal  in  each  or  the  catabolism  related  only  to 
cell  death,  the  output  of  the  two  fractions  would  be  200  to  1.  Such 
a  calculation  is,  of  course,  only  crudely  approximate.  On  the  other 
hand,  it  is  easy  to  show  directly  that  use  of  a  cell  need  not  lead  to 
appreciable  wear  as  revealed  in  catabolism.  Heavy  normal  muscular 
exertion  does  not  increase  the  output  of  nitrogen  or  of  creatinin;  sugar 
is  burned  (four-fifths  of  it  being  given  off  as  heat  and  one-fifth  appear- 
ing as  work),  but  of  chemical  evidence  of  wear  on  the  part  of  the  proto- 
plasm of  the  muscles  there  is  none.  It  may,  of  course,  have  been  so 
slight  as  not  to  have  been  appreciable  in  our  methods.  And  theoretically 
this  must  be  so,  since  we  can  no  more  imagine  a  tissue  working  without 
wear,  than  we  can  imagine  a  machine  working  without  friction.  This 
fraction  we  term  the  wear-and-tear  quotient  or  fraction,  the  protein 
needed  to  maintain  the  proplasmic  status  quo  of  the  living  functionating 
cell. 

So  far  as  we  know,  the  anabolism  of  protein  is  always  intracellular. 
Though  the  special  proteins  may  be  found  extracellular,  their  synthesis 
is  to  be  regarded  as  invariably  intracellular.    In  this  synthesis  we  must 


THE  ANAB0L1SM  OF  PROTEIN  375 

define  two  steps:  the  intracellular  digestion  of  the  serum  albumin  and 
serum  globulin;  and  the  construction  of  the  special  protein  from  the 
building  stones  of  the  same.  In  each  cell  is  performed  the  whole  act 
of  the  digestion  of  protein;  and  from  the  component  amino-acids  the 
new  proteins  are  synthesized.  The  divergencies  in  the  constitution 
of  the  special  proteins  from  the  composition  of  the  stock  proteins  are 
so  marked  that  we  are  forced  to  assume  that  the  intracellular  hydrolysis 
is  a  complete  one.  This  intracellular  hydrolysis  is,  of  course,  an  act 
of  fermentation.  And  judging  by  their  results  (they  cannot  be  well 
studied  in  experiment)  the  intracellular  proteolytic  ferments  are  of  the 
type  of  endotrypsin  seen  in  the  yeast  germ,  and  able,  like  trypsin 
followed  by  erepsin,  to  complete  the  hydrolysis  of  protein  to  the  indi- 
vidual amino-acids. 

Direct  analogies  are  to  be  observed  in  the  plant  world.  Bacteria 
do  not  utilize  directly  the  proteins  of  culture  media.  These  they  digest, 
split  into  amino-acids,  and  from  these  amino-acids  build  the  specific 
proteins  needed  in  reproduction.  Some  bacteria  cannot  digest  protein; 
they  are  dependent  upon  the  amino-acids  for  their  nutrition,  and  are 
thus  parasitic  upon  other  bacteria  that  are  able  to  hydrolyze  protein. 
Some  germs  are  very  adaptive.  Thus  Aspergillus  niger  will  build  its 
proteins  from  nitrate,  glycocoll  or  glutamic  acid  as  the  sole  source. 
In  general,  bacteria  will  utilize  only  alpha  amino-acids. 

The  sprouting  of  plant  seeds  is  another  illustration.  When  a  seed 
sprouts,  the  proteins  (as  well  as  the  carbohydrates)  are  split  into  their 
component  parts.  These  amino-acids,  or  peptids,  are  then  utilized 
in  the  formation  of  the  protein  needed  in  the  sprouting  shoots  of  the 
new  plant.  The  storage  forms  of  protein  in  the  seeds  are  usually  not 
the  forms  that  exist  in  the  growing  parts;  and  to  form  these,  the  storage 
protein  must  first  be  hydrolyzed  and  the  amino-acids  made  available 
as  building  stones. 

Illustrations  will  make  the  relations  clear.  In  some  members  of  the 
family  of  Salmo,  notably  those  of  the  Rhine  and  those  that  inhabit 
the  Western  coast  of  this  continent,  the  salmon  do  not  feed  after  enter- 
ing fresh  water  to  ascend  to  their  spawning  grounds.  They  enter 
fresh  water  in  heavy  flesh  and  very  fat,  with  the  testicles  and  ovaries 
undeveloped.  They  ascend  long  distances,  against  heavy  currents 
and  to  high  altitudes.  As  they  ascend  the  sexual  organs  are  rapidly 
developed,  and  when  the  fish  reach  the  spawning  grounds  these  glands 
are  very  massive,  weighing  possibly  twenty  times  as  much  as  when 
the  fish  entered  the  fresh  water  stream.  Since  the  fish  do  not  feed, 
the  material  for  the  growth  of  the  sexual  organs  must  have  been  derived 
from  other  tissues  of  the  body;  and  for  this  but  one  is  available,  the 
muscles.  When  the  fish  reach  the  spawning  grounds  they  are  very 
wasted,  especially  the  males.  The  muscle  substance  has  had  to  support 
not  only  the  work  of  the  ascent,  but  also  to  furnish  the  materials  for 
the  growth  of  the  ovaries  and  testicles.  The  chief  constituent  of  the 
ripe  spermatozoa  is  a  protamin,  salmin.     It  is  not  formed  directly, 


376 


THE  METABOLISM  OF  PROTEIN 


but  through  an  intermediary  stage,  a  histon.  Now  salmin  is  87  per 
cent,  arginin,  the  rest  is  serin,  prolin,  and  valin.  In  the  muscle  of  the 
salmon  are  the  serin,  prolin,  and  valin  in  the  amounts  needed,  but  there 
is  less  than  10  per  cent,  of  arginin.  The  histon  contains  about  30 
per  cent,  of  arginin.  Now  unless  the  cells  of  the  testicle  can  form  arginin 
from  the  monamino-acids  (of  which  we  have  no  evidence),  it  is  char 
that  in  order  to  form  one  part  of  protamin  ten  parts  of  muscle  protein 
must  be  destroyed.  The  muscle  protein  is  assumed  to  be  hydrolyzed 
in  situ  and  the  products  then  conveyed  to  the  testicle.  Whether  the 
muscle  protein  after  hydrolysis  is  first  reconstructed  into  blood  proteins 
and  these  then  carried  to  the  testicle;  or  whether  the  products  of  the 
hydrolysis  of  the  muscle  protein  are  carried  as  such  to  the  testicle, 
cannot  be  determined  directly.  But  carried  to  the  testicle  the  material 
is.  If  it  be  carried  to  the  testicle  in  the  form  of  amino-acids,  the  cells 
of  the  testicle  then  use  the  required  arginin,  serin,  valin,  and  prolin, 
and  the  rest  is  returned  to  the  circulation  to  be  burned.  If  the  blood 
proteins  are  the  material,  these  are  then  hydrolyzed  in  the  testicle, 
and  the  amino-acids  utilized  as  before  stated.  There  are  observations 
tending  to  show  that  serum  albumin  and  serum  globulin  are  formed 
from  the  muscle  proteins;  the  constancy  of  these  proteins  in  the  blood 
is  best  explained  on  this  view,  the  muscles  and  organs  waste,  but  the 
blood  proteins  remain  relatively  constant.  Now  protamin  could  not 
be  synthesized  from  muscle  material  unless  the  muscle  protein  were 
completely  hydrolyzed  to  the  individual  amino-acids,  because  in  the 
protamin  there  is  a  particular  linking;  there  being  six  pro  tones  (diar- 
ginyl-serin,  diarginyl-serin,  diarginyl-serin,  diarginyl-prolin,  diarginyl- 
prolin,  diarginyl- valin),  and  it  is  quite  certain  that  no  such  linkage 
occurs  in  the  muscle  protein.  , 

Collagen.  —  Collagen  is  formed  in  many  tissues.  Its  content  in 
amino-acids  as  compared  with  those  of  serum  albumin  and  globulin  is 
as  follows: 


Serum  albumin 
Serum  globulin 
Gelatin     . 


• 

n 

s 

T5 

r. 

3 

a 

A 

a 

03 

ft 
O 

| 

+ 

a 

I 

2.5 

2 

I 

.9 

B 

W 

a 

'55 

I 

3 

4) 

4.0 

a 

03 

9 

3 
8 

c 

a 
a 

< 
4.5 

a 

°3 
3 

J 

1 

< 

+ 

2.5 

1.0 

2.0 

30 

4 

+ 

1.5 

+ 

2.5 

2.5 

7.7 

8 

30 

0 

6 

7.0 

6.4 

0.0 

1.0 

14 

0.5 

8 

3 

0.0 

3.5 

20.0 


As  compared  with  the  blood  proteins,  gelatin  is  high  in  glycocoll 
(of  which  albumin  contains  none),  glutamic  acid,  and  the  pyrrols, 
low  in  the  aromatic  amino-acids.  Here,  again,  it  is  hardly  to  be  believed 
that  collagen  could  be  formed  from  the  proteins  except  after  complete 
hydrolysis  of  the  latter. 


THE  ANABOLISM  OF  PROTEIN  377 

Casein. — Casein  is  a  highly  specialized  protein.  It  is  formed  from 
the  blood  proteins  by  the  lining  cells  of  the  mammary  glands.  Casein 
contains  every  known  amino-acid  found  in  proteins  except  glycocoll; 
apart  from  this,  it  resembles  serum  globulin,  being  different  from 
serum  albumin  especially  in  a  lesser  content  of  leucin.  But  in  the 
intramolecular  arrangement  of  the  amino-acids  it  is  very  different  from 
the  two  stock  blood  proteins;  the  physical  properties  are  strikingly 
different,  the  peptones  are  different,  and  the  number  of  COOH  groups 
is  much  larger  than  in  the  blood  proteins.  Casein  is  a  perfect  protein, 
capable  of  supporting  the  synthesis  of  all  proteins,  since  the  body  can 
form  glycocoll  de  novo  or  from  other  amino-acids.  The  instance  is 
recorded  of  a  man  who,  until  he  attained  full  adult  growth,  lived  solely 
upon  milk. 

Hemoglobin. — A  highly  specialized  compound  protein  is  hemoglobin. 
It  is  a  combination  of  a  globin  and  hematin,  which  is  a  tetra-pyrrol. 
For  the  synthesis  of  this  hematin  in  the  red  marrow,  where  the  erythro- 
cytes are  generated,  the  pyrrol  of  the  stock  proteins  of  the  blood  is 
alone  available,  so  far  as  we  know.  In  the  molecule  of  protein  the 
pyrrol  bodies  are  intimately  bound  with  the  amino-acids.  To  set 
them  free  in  order  that  they  may  be  linked  together  with  iron  to 
form  hematin,  complete  hydrolysis  of  the  protein  molecule  must  be 
required.  Here  is  an  instance  where  protein  is  catabolized  in  order 
that  one  constituent  of  the  molecule  may  be  made  available  for  a 
special  synthesis. 

Mucins. — The  mucins  again  are  very  different  proteins,  though 
formed  from  the  stock  proteins  by  lining  epithelial  cells.  The  mucins 
are  difficult  of  isolation  and  analysis.  It  is  known,  however,  that  they 
are  poor  in  arginin,  lysin,  cystin,  aspartic,  and  glutamin  acids,  contain 
usual  amounts  of  leucin,  tyrosin,  phenylalanin,  and  tryptophan,  and 
are  very  rich  in  glucosamin,  from  20  to  30  per  cent.  This  glucosamin 
is  intimately  bound  with  the  COOH  group  of  the  normal  amino-acids 
by  its  NH2  group,  it  is  not  localized  in  one  of  the  peptone  groups,  but 
is  intimately  incorporated  in  the  whole t  molecule.  Here  again  it  is 
not  possible  to  understand  the  synthesis  of  this  protein  except  upon  the 
assumption  that  the  parent  cell  had  the  full  quota  of  free  amino-acids 
at  its  disposal. 

Special  Proteins. — It  is  not  possible  to  predicate  the  derivation  of 
the  different  special  proteins  from  either  serum  albumin  or  serum 
globulin.  Most  of  the  organ  globulins  resemble  closely  serum  globulin. 
Naturally  a  protein  rich  in  glycocoll  could  not  have  been  derived 
from  serum  albumin  directly.  Many  of  the  proteins  of  the  connective 
tissue  resemble  serum  albumin  in  many  ways  and  there  is  a  general 
similarity  in  the  chemical  and  physical  properties  of  these  proteins. 
But  some  of  them  are  one-fourth  glycocoll,  while  others  are  devoid 
of  glycocoll.  The  more  the  special  proteins  are  studied,  the  more 
complex  become  the  findings.  And  one  might  as  well  come  to  the 
belief  first  as  last,  that  in  the  cells  in  which  these  special  proteins  are 


378  THE  METABOLISM  OF  PROTEIN 

synthesized,  the  blood  proteins  are  broken  into  their  individual  amino- 
acids,  since  this  state  of  affairs  alone  affords  the  functionating  cells 
free  scope  for  their  reconstructions. 

Synthesis  of  Amino-acids. — An  important  question  concerns  the 
possibility  of  the  synthesis  of  amino-acids  by  cells  of  the  higher  animal 
body.  If  amino-acids  can  be  synthesized,  the  ultimate  dependence  of 
the  body  upon  the  proteins  of  the  diet  is  lessened.  For  all  the  amino- 
acids  definite  answer  cannot  be  given.  It  is  certain  that  cystin  and 
the  aromatic  amino-acids  cannot  be  synthesized  in  the  animal  body. 
The  body  has  not  the  power  to  build  the  benzene  ring,  nor  can  it  com- 
bine this  ring  with  an  amino-acid.  It  is  possible  that  phenylalanin 
and  tyrosin  are  convertible  into  each  other,  but  one  or  the  other  must 
be  preformed.  Nor  can  the  body  combine  sulphur  with  an  amino- 
acid,  the  cystin  must  be  presented  preformed.  There  is  also  data 
making  it  very  doubtful  whether  the  diamino-acids  can  be  formed  in 
the  body.  Chemically  it  seems  possible  that  lysin  might  arise  from 
glucose  or  from  the  condensation  of  two  molecules  of  alanin;  the  body 
splits  arginin  into  ornithin  and  urea,  but  so  far  as  we  know  cannot 
unite  them.  Asparagin  spares  protein  in  herbivora,  but  does  not  so 
act  in  carnivora.  This  may  be  interpreted  to  mean  that  in  herbivora 
aspartic  acid  can  be  converted  into  other  amino-acids,  while  in  carnivora 
this  is  impossible.  There  is  no  doubt  that  the  body  can  form  glycocoll 
in  large  amounts.  This  is  proved  directly  by  the  maintenance  of  body 
growth  on  a  diet  of  casein,  which  contains  no  glycocoll.  And  by  the 
administration  of  benzoic  acid  it  can  be  shown  that  the  body  has  the 
power  of  making  glycocoll  available  in  amounts  far  in  excess  of  the 
protein  catabolized  during  the  period  of  the  experiment.  Possibly 
in  some  way,  acetic  acid  and  ammonia  are  united  to  form  glycocoll. 
It  was  elsewhere  stated  that  animals  may  be  kept  in  nitrogen  equilib- 
rium with  mixtures  of  amino-acids.  This  experiment  succeeds  even 
if  glycocoll  be  absent,  i.  e.,  the  body  must  synthesize  glycocoll.  If, 
in  the  same  experiment,  tryptophan  or  the  related  tyrosin  and  phenyl- 
alanin are  omitted,  the  experiment  fails.  On  the  whole,  we  may  for 
the  present  assume  that  except  glycocoll,  all  the  amino-acids  must 
exist  preformed  in  the  proteins  of  the  diet  in  amounts  sufficient  to 
offer  the  needed  units.  Gelatin,  which  cannot  support  the  protein 
metabolism,  owing  to  its  lack  of  aromatic  amino-acids,  become  fully 
competent  as  a  diet  protein  when  combined  with  an  equal  part  of 
other  proteins  containing  the  usual  amounts  of  these  groups. 

It  is  possible  that  if  we  could  define  exactly  the  body  needs  in  cystin 
and  phenyl-amino-acids,  we  could  determine  the  minimal  protein 
requirements  of  the  whole  body.  No  matter  in  how  much  excess  the 
other  amino-acids  may  be  present,  at  least  that  much  protein  is  daily 
necessary  as  will  furnish  the  needed  thio  and  aromatic  groups.  And 
since  different  proteins  contain  different  amounts  of  thio  and  aromatic 
amino-acids,  the  experiments  might  be  so  varied  as  to  afford  data 


THE  ANABOLISM  OF  TR0TE1N  379 

from  which  could  be  calculated  the  amount  of  protein  necessary  in  the 
diet  to  maintain  the  body  in  tissue  equilibrium. 

The  possibility  of  the  neo-formation  of  amino-acids  in  the  animal 
body  by  conjugation  of  NH2  group  with  fatty  acids,  has  as  stated 
usually  been  denied  (outside  of  glycocoll),  even  as  a  qualitative  reac- 
tion. Recently,  however,  experimental  evidence  has  been  adduced 
in  favor  of  such  synthesis.  The  proposition  amounts  to  a  reversion, 
in  a  circuitous  manner  possibly,  of  the  reaction  of  deaminization. 
When  phenyl- a-keton-butyric  or  phenyl-oxy-butyric  acid  is  fed  to 
animals,  an  acetyl-amino-butyric  acid  is  eliminated.  It  has  been  long 
known  that  amino-acids  may  be  oxidized  in  the  body  to  the  correspond- 
ing a-ketonic  acid,  which  is  the  reversion  of  the  above  reaction.  Per- 
fusion experiments  on  the  liver  have  also  indicated  that  alanin  is  formed 
from  lactic  acid,  a  direct  illustration.  Such  a  reaction,  if  done  as  a 
functional  act,  amounts  to  the  assimilation  of  nitrogen  in  the  state 
of  ammonia,  a  faculty  that  has  been  hitherto  vested  solely  in  plants 
and  lower  forms  of  animal  life.  Without  wishing  to  deny  the  occur- 
rence of  the  qualitative  reactions  described,  it  is  quite  another  thing 
to  assume  that  they  illustrate  quantitative  functional  reactions.  Our 
total  knowledge  of  the  details  of  the  catabolism  of  protein  is  against 
such  a  proposition.  The  mass  relations  that  exist  in  the  liver  and 
tissues  must  operate  against  such  a  synthesis.  Were  we  to  administer 
as  food  the  several  fatty  acids,  it  is  certain  that  they  would  be  burned 
in  the  liver  or  converted  into  sugar,  instead  of  uniting  with  ammonia 
to  form  amino-acids,  since  the  concentration  in  the  liver  of  ammonia 
derived  from  the  endogenous  catabolism  of  protein  must  be  extremely 
low.  As  a  matter  of  direct  interest  in  questions  of  metabolism,  the 
qualitative  reaction  may  prove  to  be  of  importance.  But  since  a  diet 
does  not  and  cannot  contain  the  appropriate  fatty  acids,  except 
already  preformed  as  amino-acids  in  protein,  the  possibility  of  ammonia 
operating  in  such  a  closed  inner  circle — set  free  in  catabolism  of  tissue, 
recombined  into  proteins  of  blood,  anabolized  again  into  tissue — is 
entirely  out  of  the  question,  even  in  part. 

Incomplete  Proteins  and  Endogenous  Catabolism. — This  problem  has 
been  approached  experimentally  from  another  direction  through 
investigations  bearing  on  the  ability  of  incomplete  proteins  to  sustain 
the  endogenous  catabolism.  The  plan  of  such  investigations  is  to 
place  an  animal  upon  a  nitrogen-free  diet  of  carbohydrate,  or  carbo- 
hydrate and  fat,  with  the  necessary  salts.  When  the  nitrogenous 
elimination  falls  to  a  constant  level,  this  is  taken  to  represent  the 
minimal  basis  of  endogenous  protein  catabolism.  Incomplete  proteins 
— gliadin,  zein,  and  gelatin  have  been  tested — are  then  administered 
in  amounts  corresponding  to  the  urinary  output  of  nitrogen.  Under 
these  circumstances  a  nitrogen  balance  is  never  attained.  In  the  case 
of  gliadin  and  zein,  about  one-fourth  more  nitrogen  is  eliminated  than 
was  contained  in  the  input;  in  the  case  of  gelatin  the  inefficiency  is 
much  greater;  there  is  50  per  cent,  excess  nitrogen  in  the  urine.    While 


380  THE  METABOLISM  OF  PROTEIN 

these  proteins  are  all  incomplete,  they  are  different;  zein  lacks  glycocoll, 
tryptophan,  and  lysin;  gliadin  lacks  lysin;  gelatin  lacks  cystin,  tyrosin, 
and  tryptophan.  It  is  clear  from  the  results  that  these  incomplete 
proteins  have  always  a  certain  and  in  some  cases  a  surprising  power, 
in  replacing  the  body  protein  disintegrated  in  the  endogenous  catab- 
olism.  Growth,  however,  is  never  to  be  attained  under  such  circum- 
stances. It  has  been  suggested  that  these  results  indicate  that  the 
endogenous  metabolism  for  maintenance  is  different  than  for  growth; 
and  that,  furthermore,  in  the  utilization  of  protein  by  cells,  complete 
cleavage  is  not  essential.  Viewed  closely,  however,  these  two  inferences 
are  not  warranted.  It  might  be  possible,  in  the  first  place,  that  one 
amino-acid  could  be  formed  from  another,  certainly  the  glycocoll  could 
be  so  derived.  Lysin  might  be  derived  from  glucose.  But  it  is  impossible 
to  assume  the  synthesis  of  tyrosin,  tryptophan,  and  cystin  in  the 
animal  body.  However,  it  is  possible  to  seek  another  source  for  these. 
It  is  possible  that  in  the  excess  of  nitrogen,  eliminated  over  the  input 
in  the  protein  under  investigation,  is  included  nitrogen  of  body  protein 
catabolized  to  furnish  tyrosin,  cystin,  tryptophan,  and  lysin,  just  as 
the  salmon  catabolizes  muscle  to  furnish  arginin  for  the  ripening  testicle. 
None  of  the  amino-acids  named  exist  in  large  amounts  in  the  glandular 
protoplasm ;  and  without  the  catabolism  of  greater  amounts  of  different 
tissue  protein  than  indicated  in  the  nitrogen  deficit,  it  is  possible  that 
the  needed  particular  amino-acids  could  be  obtained  wherewith  to 
maintain  the  endogenous  metabolism  in  accordance  with  the  current 
conception  of  protein  restitution.  There  is  now  a  considerable  literature 
on  the  power  of  gelatin  to  spare  protein  (gelatin  replaces  protein, 
being  an  incomplete  protein;  it  does  not  spare  protein  by  virtue  of  the 
sugar  it  can  yield).  Two-thirds  gelatin  and  one-third  other  protein 
will  hold  a  dog  in  nitrogenous  balance  at  the  fasting  figure.  Gelatin 
spares  most  largely  protein  being  burned  for  dynamogenetic  purposes; 
it  can  be  used  for  anabolism  by  having  added  to  it  the  missing  cystin, 
tyrosin,  and  tryptophan  derived  by  the  catabolism  of  indifferent  body 
protein.  If  the  missing  cystin,  tryptophan,  and  tyrosin  are  added 
directly  as  amino-acids,  gelatin  becomes  a  complete  protein  and  can 
sustain  nitrogenous  equilibrium. 

Nevertheless,  experiments  have  shown  that  it  is  possible  to  maintain 
rats  over  long  periods  with  food  free  of  tryptophan.  This  result  sug- 
gests that  it  is  possible  for  the  body  to  form  tryptophan  from  the 
benzene  ring  introduced  in  tyrosin  and  phenylalanin. 

Conjugation  of  Special  Proteins. — The  conjugation  of  the  special 
protein  with  the  other  substances  that  participate  in  the  formation 
of  the  compound  or  conjugated  proteins  (nucleoproteins,  glycoproteins, 
phosphoproteins,  lecithoproteins,  hemoglobins,  chromoproteins)  is  accom- 
plished  in  the  particular  cells  concerned.  Some  of  these  conjugated 
proteins  resemble  esters,  others  resemble  glucosids.  The  mechanism 
of  these  conjugations  is  entirely  unknown.  In  some  of  these  compounds 
the  protein  seems  to  functionate  as  a  whole,  and  cannot  be  itself  hydro- 


THE  ANABOLISM  OF  PROTEIN  381 

lyzed  until  it  has  been  set  free  from  the  other  substance.  In  others 
this  does  not  seem  to  hold,  the  protein  within  the  conjugation  is  subject 
to  hydrolysis.  Pepsin  and  trypsin  split  all  these  conjugations.  In  the 
tryptic  digestion  of  some  of  these,  as  in  the  case  of  hemoglobin  at  weak 
alkaline  reaction,  tyrosin  is  set  free  before  cleavage  into  globin  and 
hematin  appears  to  be  accomplished.  On  the  other  hand,  hemoglobin 
is  split  by  pepsin  HC1  before  the  protein  fraction  is  demonstrably 
digested.  In  the  case  of  the  lipoid-protein  complex  of  organs,  the  fat 
is  in  firm  combination  and  is  not  recovered  except  after  a  tryptic 
digestion. 

Formation  of  Special  Tissue  Proteins. — The  formation  of  the  special 
tissue  proteins  depends  solely  on  the  need,  it  is  apparently  not  possible 
to  engorge  cells  with  their  special  proteins,  except  following  periods  of 
starvation.     The  adaptation  is  beautifully  shown  in  the  case  of  the 
gravid  uterus.    The  number  of  cells  in  the  uterus  is  increased  during 
pregnancy,  and  the  size  of  the  individual  cells  greatly  enlarged.    This 
is,   of  course,   accomplished  through  the   synthesis  of  extra  muscle 
protein.    Following  delivery,  during  involution,  these  overgrown  cells 
become  reduced  to  their  normal  dimensions.    This  must  be  explained 
as  due  to  the  hydrolysis  of  the  now  excessive  protoplasm,  the  extrusion 
of  the  soluble  products  into  the  circulation,  later  to  suffer  deaminization 
and  oxidation.     Here  we  see  a  special  instance  of  an  intracellular 
growth,  followed  later  by  reversion  to  the  original  status.    The  different 
cells  of  the  body  are  of  very  different  orders  of  magnitude;  they  may 
in  general  be  assumed  to  have  an  intensity  of  metabolism  directly 
proportional  to  their  cellular  dignity,  and  a  duration  of  life  inversely 
proportional  to  their  cellular  rank.    The  cells  of  the  common  connective 
tissues  can  be  deprived  of  blood  supply  for  hours  without  injury;  the 
cells  of  the  central  nervous  system  die  within  a  few  moments  when 
deprived  of  blood  supply.     It  may  be  as  confidently  stated  that  the 
cells  of  fasciae  and  tendon  have  a  long  span  of  life,  and  that  the  cells 
of  the  central  nervous  system  have  a  short  span  of  life.    The  anabolic 
synthesis,  cell  for  cell,  will  therefore,  be  greater  for  the  special  proteins 
of  the  cells  of  high  rank.     The  growth  of  the  muscular  system  from 
birth  is  growth  by  enlargement  of  muscle  cells  solely,  not  by  multipli- 
cation; a  certain  muscle  in  the  newborn  has  as  many  cells  as  the  same 
muscle  at  full  growth.    In  hypertrophy  of  the  heart  and  in  the  growth 
of  the  gravid  uterus,  however,  increase  in  number  of  cells  is  also  held 
to  occur.    The  wasting  of  the  muscles  of  the  salmon  during  the  anadrom- 
ous  migration  is  not  a  diminution  in  number  of  cells  but  a  shrinking 
in  the  mass  of  the  cells.    Whether  the  rule  of  increase  in  dimensions 
but  not  in  numbers  holds  true  for  the  nervous  system  has  not  been 
determined. 

Adaptation  in  Anabolic  Function. — Feeding  experiments  in  growing 
animals  have  yielded  very  interesting  results  indicative  of  adaptations 
in  the  anabolic  functions.  When  a  growing  organism  is  underfed,  one 
of  two  things  may  happen :  growth  may  be  interrupted  or  growth  may 


382  THE  METABOLISM  OF  PROTEIN 

be  maintained  through  a  shifting  of  the  anabolic  functions.    If  the  diet 

be  too  insufficient,  growth  is  checked  and  death  will  result.     But  if 

the  diet  be  so  arranged  that  the  animal  can  maintain  weight  and 

nitrogenous  equilibrium,  growth  is  continued.      In  order  for  growth 

to  be  thus  maintained,  tissue  of  low  grade  must  be  sacrificed  to  tissue 

of  high  grade,  just  as  in  the  migrating  salmon  muscle  is  sacrificed  to 

testicle  and  ovary.     In  successful  experiments  in  animals  growth  is 

maintained,  the  skeleton  increases  in  dimensions,  the  glandular  organs 

are  conserved  and  the  central  nervous  system  is  held  intact;  muscle 

and  connective  tissue  are  catabolized  and  from  the  products  of  their 

hydrolysis  the  materials  are  derived  wherewith  the  cellular  anabolisms 

are  maintained.     With  pronounced  degree  of  such  underfeeding,  the 

proteins  of  the  blood  fall  below  normal.    When  later  normal  feeding  is 

practised,  the  depleted  muscular  and  connective  tissues  are  restored ;  and 

it  is  remarkable  to  what  extent  such  processes  of  restoration  can  proceed, 

so  that  after  a  time  the  animals  quite  equal  normal  animals.    There  is, 

of  course,  an  intensity  and  a  duration  of  such  underfeeding  that  lead 

to  loss  that  is  irreparable;  the  animals  remain  "runts."    These  facts 

have  been  worked  out  both  for  carnivora  and  herbivora,  and  afford 

concrete  demonstration  of  the  biological  impulses  in  the  functions 

of  protein  anabolism.     The  condition  in  infancy  sometimes   termed 

infantilism  probably  represents  such  a  condition  of  undernutrition,  the 

result  either  of  improper  feeding  or,  more  likely,  of  reduced  digestion 

and  assimilation.     While  it  is  true  that  in  young  children  increase 

in  weight  should  accompany  increase  in  length  of  skeleton,  it  is  not 

equally  true  that  in  older  children  the  same  rule  holds.    It  is  common 

to  find  in  boys  nearing  puberty,  pronounced  increase  in  height  without 

increase  in  weight,  to  be  followed  later  by  recovery  in  weight,  the 

two  processes  occurring  in  sequence.    Apparently  there  is  at  the  age 

of  puberty  in  boys  an  impulse  to  grow  that  may  exceed  the  powers  of 

digestion  and  assimilation,  and  under  these  circumstances  tissues  of 

lower  order  are  for  a  time  catabolized  to  support  the  growth  of  tissue 

of  higher  order;  when  the  excessive  growth  ceases,  the  defects  are 

repaired. 

The  stock  proteins  of  the  blood  are  also  the  material  for  the  synthesis 
of  the  important  pyrimidin  and  purin  bases  of  the  purin  metabolism. 
The  direct  synthesis  of  these  substances  from  protein  is  well  illustrated 
in  the  hatching  of  birds.  Eggs  contain  no  purin  or  pyrimidin  and 
all  the  purin  and  pyrimidin  of  the  nuclei  of  the  cells  of  the  hatched 
chicks  have  been  synthesized  from  albumin.  Milk  contains  no  purin 
or  pyrimidin;  and  from  casein,  indirectly  via  the  blood  proteins,  is 
synthesized  all  the  nucleic  material  of  the  growing  infant.  These 
matters  will  be  discussed  in  the  proper  context  under  the  nucleic 
metabolism.  We  also  regard  the  proteins  as  the  parent  substance  of 
creatin. 

There  are  no  known  pathological  variations  in  the  anabolism  of 
protein,  either  qualitative  or  quantitative.     This  applies  as  well  to 


THE  CATABOLISM  OF  PROTEIN  383 

the  utilization  or  assimilation  of  the  products  of  digestion  as  to  the 
formation  of  the  special  proteins  and  nucleins.  There  are  investiga- 
tions tending  to  show  that  the  special  proteins  of  malignant  neoplasms 
are  different  from  those  of  the  prototype  cells.  In  myxedema  the 
skin  is  infiltrated  with  a  mucoid  substance,  that  has  been  regarded 
as  different  from  normal  mucins.  In  the  degenerations  of  tumors  of 
certain  types  also,  proteins  of  seemingly  abnormal  appearances  occur. 
While  there  is  every  theoretical  reason  to  believe  that  under  condi- 
tions of  disease  such  deflections  in  the  qualitative  formation  of  special 
tissue  proteins  could  occur,  the  investigations  to  date  have  not  been 
carried  out  with  the  degree  of  thoroughness  necessary  to  establish 
such  differentiation. 


THE  CATABOLISM  OF  PROTEIN 

Before  proceeding  to  the  discussion  of  concrete  acts  of  catabolism 
of  protein  it  will  be  of  advantage  to  elucidate  the  whole  situation. 
The  catabolism  of  protein  may  be  stated  to  include  five  rubrics: 

(a)  Of  this  there  are  two  fractions:  firstly,  the  catabolism  of  protein 
derived  from  cells  that  have  died,  each  cell  having  like  all  unicellular 
organisms  a  limited  term  of  life;  secondly,  of  protein  assumed  to  have 
been  cast  off  as  the  expression  of  intracellular  wear  and  tear.  The  first 
fraction  results  from  the  death  of  the  cell,  the  second  (the  wear-and- 
tear  quotient),  is  incidental  to  the  life  of  the  cell.  This  catabolism 
continues,  of  course,  during  starvation. 

(6)  The  catabolism  of  the  amino-acids  resorbed  from  the  products 
of  the  digestion  of  protein  and  not  suited  to  the  synthesis  of  the  stock 
proteins  of  the  blood.  When  proteins  on  digestion  yield  certain  amino- 
acids  in  larger  amounts  than  can  be  utilized  in  the  synthesis  of  serum 
albumin  or  globulin,  so  long  as  we  believe  these  are  not  convertible 
into  other  amino-acids  there  is  for  them  no  other  fate  than  to  be  catab- 
olized,  probably  in  the  liver.  For  certain  proteins  in  the  diet  there 
must  be  rather  large  excesses  of  certain  amino-acids;  in  all  cases  there 
must  be  some.  Thus  gliadin  contains  36  per  cent,  of  glutamic  acid, 
and  elastin  25  per  cent,  of  glycocoll,  far  more  than  can  be  used  in  the 
blood  proteins.  It  is  possible  to  assume,  as  will  be  elsewhere  explained, 
that  in  this  fraction  lies  in  part  the  explanation  of  the  specific  dynamic 
action  of  protein. 

(c)  The  catabolism  of  superfluous  amino-acids  derived  from  serum 
albumin  and  serum  globulin  within  the  cells  of  the  body  prior  to  the 
synthesis  of  the  special  proteins.  All  the  amino-acids  of  the  stock  pro- 
teins are  not  needed  in  the  special  proteins.  When  histons  and  protamins 
are  synthesized,  large  amounts  of  diamino-acids  are  needed  and  conse- 
quently more  monamino-acids  will  be  set  free  than  are  required.  In 
the  synthesis  of  all  special  proteins  it  may  be  inferred  that  more  or 
less  of  the  amino-acids  of  the  stock  proteins  will  be  superfluous.    These 


384  THE  METABOLISM  OF  PROTEIN 

ammo-acids  we  believe  to  be  catabolized,  but  we  cannot  hope  to  measure 
this  fraction.  Fractions  b  and  c,  as  well  as  a,  must  be  large  during  the 
period  of  growth,  when  the  ratio  of  protein  metabolism  to  body  weight 
is  high,     a  +  6  +  c  represents  the  endogenous  protein  catabolism. 

(d)  The  catabolism  of  the  excess  of  stock  proteins  of  the  blood, 
that  quantity  over  and  above  the  amount  needed  to  support  the 
synthesis  of  the  special  proteins.  The  synthesis  of  special  protein, 
the  anabolism  of  protein,  is  not  a  constant  but  an  adaptable  factor, 
as  will  be  explained.  But  whatever  its  extent  on  a  particular  day, 
the  needs  in  amino-acids  occasioned  thereby  are  covered  by  the  stock 
proteins.  Obviously  b  and  d  have  the  same  meaning,  they  are  super- 
fluous. And  all  stock  protein  formed  from  the  diet  of  one  day  over  and 
above  the  needs  of  the  synthesis  of  that  day  is  promptly  catabolized. 
It  is  just  as  though  a  stream  had  two  outlets  and  one  inlet,  the  inlet 
and  the  one  outlet  being  regulable.  The  outflow  from  the  unregulated 
outlet  will  be  the  difference  between  the  input  and  the  outflow  of  the 
regulable  outlet.  If  with  a  constant  input  the  regulable  outlet  be 
raised,  more  will  flow  from  the  open  outlet;  if  the  regulable  outlet  be 
lowered,  less  will  flow  out  through  the  open  outlet.  If  the  regulable 
outlet  be  constant,  increased  input  will  result  in  increased  outflow 
from  the  open  outlet;  if  the  intake  be  reduced  less  will  flow  out  from 
the  open  outlet.  It  is  a  reciprocal  relation  between  three  factors,  a 
relation  of  equilibrium.  It  may  be  illustrated  in  another  way.  It  is 
just  as  though  a  factory  received  each  day  a  shipment  of  perishable 
material,  from  which  it  prepared  a  conserved  product  for  immediate  use. 
Whatever  was  left  over  of  the  raw  material  each  night  was  destroyed.  If 
the  use  of  the  conserved  product  rose,  then  more  raw  material  was 
worked  up  and  there  was  less  to  throw  away.  If  less  of  the  conserved 
product  was  used,  there  was  less  to  make  up  and  more  of  the  raw 
material  to  throw  away.  If  with  a  fixed  consumption  of  the  conserved 
product  the  intake  of  raw  material  was  cut  down,  there  was  less  to 
destroy;  if  the  intake  was  increased,  there  was  more  to  dispose  of. 
Fraction  d  represents  the  exogenous  protein  catabolism. 

The  maintenance  of  a  constant  concentration  of  protein  in  the  blood 
plasma  under  varying  experimental  conditions  indicates  the  stability 
of  the  station  of  equilibrium.  If  a  dog  be  bled  a  third  of  his  blood 
and  the  volume  replaced  with  isotonic  salt  solution,  in  a  surprisingly 
short  time  the  blood  plasma  will  be  found  to  have  recovered  its  normal 
content  of  protein,  derived  largely  from  body  cells  of  lesser  dignity. 
The  maintenance  of  the  stock  proteins  of  the  blood  during  starvation 
indicates  the  same  thing,  in  a  slower  manner.  On  the  contrary,  if 
dog  serum  be  injected  intravenously  into  a  dog,  a  proportionate  excess 
of  nitrogen  will  be  eliminated  in  the  urine  in  a  day  or  two.  And  if 
the  dog  eat  the  same  excess  of  protein,  the  same  elimination  occurs. 
In  a  word,  under  all  circumstances  the  body  endeavors  to  maintain  a 
fixed  concentration  of  protein  in  its  blood  plasma  and  tissues.  The 
situation  in  the  body  is  not  so  rigid  as  here  illustrated,  because  of  the 


THE  CATABOLISM  OF  PROTEIN  385 

faculty  of  adaptation  and  compensation,  but  the  fundamental  relations 
are  as  stated.    The  body  has  little  storage  capacity  for  protein. 

In  starvation,  another  factor  of  catabolism  (e)  makes  its  appearance. 
Factor  (a)  persists.  When  now  during  the  course  of  a  starvation  (or 
in  hibernation)  the  wasting  of  the  most  important  tissues  reaches  a 
certain  point,  these  cells  are  maintained  by  syntheses  from  the  stock 
proteins.  These  in  turn  are  maintained  by  syntheses  from  the  less 
important  proteins,  those  of  the  muscle  and  connective  tissues.  Now 
in  the  formation  of  blood  proteins  from  the  protein  of  muscle  and 
connective  tissue,  amino-acids  of  one  or  another  kind  will  be  super- 
fluous, and  these  will  be  catabolized. 

It  will  be  best  first  to  deal  with  the  questions  in  a  purely  qualitative 
way.  The  catabolism  of  a  merits  first  description.  We  will  follow 
it  to  the  stage  of  amino-acids.  Then  we  will  take  up  the  catabolism 
of  rubric  d.  This  we  will  carry  to  the  stage  of  amino-acids.  To  these 
may  then  be  joined  b,  c,  and  e.  From  this  point  we  will  trace  the  fate 
of  each  known  amino-acid  until  the  state  of  excrementation  is  reached. 
Thereafter  the  quantitative  relations  will  be  elucidated  as  far  as  is  pos- 
sible. The  catabolism  of  nuclein  will  receive  a  separate  consideration. 
In  some  places  facts  furnish  the  basis  for  theory;  in  other  instances, 
sound,  general  theory  must  be  used  to  interpret  facts  of  undoubted 
occurrence  but  indeterminate  meaning. 

There  are  clearly  four  reactions  concerned  in  the  catabolism  of 
protein:  the  hydrolysis  of  the  molecule  of  protein;  the  formation  of 
glucose  from  amino-acids;  the  deaminization  of  the  amino-acids;  and 
the  oxidation  of  NH2  and  of  the  fatty  acids. 

The  Hydrolysis  of  Protein  within  the  Body. — The  hydrolysis  of  the 
protein  of  the  cells  that  are  dead  presents  no  difficulties  to  compre- 
hension. The  phenomenon  of  postmortem  autolysis  gives  so  clear  an 
illustration  that  there  can  be  no  doubt  of  the  physiological  facts.  If 
a  liver  be  removed  from  the  body  and  allowed  to  lie  at  ordinary  tem- 
peratures under  sterile  conditions,  it  will  be  found  after  a  few  days 
that  the  tissue  has  become  softened,  the  amount  of  coagulable  protein 
has  been  greatly  reduced,  or  may  indeed  be  absent,  and  on  analysis 
the  organ  will  be  found  to  contain  large  amounts  of  proteoses,  peptone, 
amino-acids,  some  urea  and  ammonia.  The  autolysis  of  the  liver  is 
not  a  process  confined  to  the  proteins;  it  involves  glycogen,  arginin, 
nucleic  acid,  and  to  a  slight  extent  the  fats — each  carried  on,  of  course, 
by  the  appropriate  ferment.  This  self-digestion  is  thus  accomplished 
through  the  activity  of  intracellular  ferments  which  continue  to  func- 
tionate as  catalytic  agents  after  the  death  of  the  cells.  Just  as  dried 
and  powdered  yeast  cells  contain  ferments  that  will  digest  the  cell 
residues  when  placed  in  solution,  so  the  liver  cells  contain  an  endo- 
trypsin  which  is  able  to  accelerate  the  hydrolysis  of  the  protein  of  the 
hepatic  protoplasm  to  amino-acids.  This  ferment  action  does  not 
proceed  from  the  blood,  whose  influence  can  be  ruled  out.  Now  in  the 
postmortem  autolysis  of  the  liver  we  observe,  en  masse,  the  identical 
25 


386  THE  METABOLISM  OF  PROTEIN 

reaction  that  we  must  believe  occurs  in  each  liver  cell  when  worn  out 
it  dies.  Cellular  catabolism  therefore  means,  in  part,  unicellular 
autolysis.  So  long  as  the  cell  is  living  its  protoplasm  remains  intact; 
so  soon  as  it  dies,  it  is  digested  by  the  ferments  contained  within  itself. 

In  the  hydrolysis  of  protein  within  the  body,  peptones  are,  of  course, 
formed,  which  are  obviously  not  toxic.  Peptones  formed  from  foreign 
proteins  in  the  digestive  tract  are  toxic;  those  formed  in  the  body  from 
its  own  proteins  are  not  toxic.  This  difference  between  isopeptone 
and  heteropeptone  we  regard  as  resident  in  the  intramolecular  linking 
of  the  amino-acids. 

The  hydrolysis  of  the  fraction  of  protein  in  the  protoplasm  of  the 
functionating  cell,  that  for  reasons  of  wear  and  tear  must  be  daily 
replaced,  we  must  regard  as  included  in  the  same  reaction.  There 
is  apparently  a  difference  between  protoplasmic  protein  and  mere 
protein  that  is  to  be  regarded  as  a  cell  inclusion.  When  the  fraction 
of  worn  protoplasm  is  deprotoplasmatized,  it  becomes  subject  to  hydro- 
lysis. Just  how  we  are  to  picture  to  ourselves  this  condition  in  proto- 
plasm that  renders  its  protein  resistant  to  digestion  is  as  yet  impossible 
of  definition.  We  can  say  that  it  lies  in  the  physico-chemical  state  of 
the  lipoid-protein  complex,  but  that  is  a  concept  and  not  a  definition. 
Be  it  what  it  may,  it  is  the  same  fact  that  prevents  the  unicellular 
yeast  cell  from  being  digested  while  alive  by  the  ferments  that  rapidly 
digest  it  after  it  is  dead.  To  term  it  a  vital  force  is  merely  to  still  the 
question  by  filling  the  ear.  The  concept  "anti-ferment"  is  still  largely 
verbal. 

The  hydrolysis  of  the  excess  of  circulating  protein,  the  excess  of  the 
input  over  the  needs  of  the  body  for  syntheses,  is  not  well  understood. 
It  could  occur  either  in  the  circulating  blood  or  in  cells.  It  is  difficult 
to  conceive  it  as  occurring  in  the  circulating  blood.  There  is  a  trypsin 
in  the  blood — or  at  least  in  the  blood  corpuscles — and  it  would  not 
be  proper  to  rule  this  ferment  out  because  in  tests  in  glass  it  seems  to 
be  of  weak  activity.  But  the  idea  of  a  ferment  action  that  is  so  limited, 
stopping  short  in  a  system  where  the  substrate  is  so  concentrated  as 
is  protein  in  the  blood  plasma,  is  difficult  of  entertainment.  A  less 
objectionable  idea  is  that  the  blood  unloads  its  excess  of  stock  protein 
upon  the  cells.  Within  these  cells  it  then  would  occupy  the  same 
position  metabolically  as  the  protein  of  the  wear  and  tear  considered 
in  the  last  paragraph.  It  would  occupy  within  the  cell  the  same  posi- 
tion that  glucose  occupies  in  the  muscle  cell,  where  it  is  being  burned 
without  being  a  part  of  the  protoplasm.  It  has  been  elsewhere  pointed 
out  that  when  an  excess  of  protein  is  catabolized,  the  sugar  and  urea 
derived  therefrom  do  not  make  their  appearance  in  the  urine  at  the 
same  time.  This,  however,  may  be  an  expression  of  elimination  and 
not  of  metabolism ;  and  in  any  event  does  not  give  any  suggestion  as  to 
whether  the  catabolism  of  the  excess  of  protein  occurs  within  the  cells 
or  without.  It  will  be  later  pointed  out  that  the  catabolism  of  protein 
from  protoplasm  is,  so  to  speak,  more  effectively  accomplished  than 


THE  CATABOLISM  OF  PROTEIN  387 

is  the  case  with  the  catabolism  of  the  excess  of  protein  derived  from 
the  diet.  This  fact  again  does  not  argue  for  any  site  or  modus  of 
catabolism  of  the  extra  protein.  The  question  must  be  left  open, 
with  the  statement  that  general  considerations  make  it  most  probable 
that  the  reaction  occurs  within  the  cells;  and  of  the  cells,  most  likely 
in  the  liver.  From  this  point  of  view  we  may  regard  the  liver  as  dis- 
posing of  the  excess  of  protein  by  catabolism  just  as  it  disposes  of 
the  excess  of  glucose  by  the  formation  of  glycogen. 

Closely  related  to  the  question  of  the  site  of  catabolism  of  the  ex- 
ogenous protein  is  the  question  of  the  state  in  which  it  exists  within 
the  body.  The  distinction  between  the  protein  that  is  a  part  of  the 
cellular  protoplasm  and  the  excess  of  protein  that  simply  passes  through 
the  body,  so  to  speak,  in  course  of  catabolism  has  been  the  occasion 
of  many  famous  controversies  in  the  literature  of  physiology.  The 
former  is  usually  described  under  the  term  protoplasmic  protein,  the 
protein  that  in  the  complex  with  lipoid  and  carbohydrate,  ion,  and 
salt  constitutes  the  physico-chemical  state  of  the  protoplasm  of  the 
cell.  The  excess  of  protein,  commonly  termed  "dead"  or  "circulating 
protein/'  "storage,"  "reserve,"  "labile  protein,"  is  not  held  to  exist  in 
such  a  physico-chemical  complex.  Where  it  is  stored  and  how,  as  well  as 
where  it  is  catabolized,  we  do  not  know  experimentally.  As  stated,  in 
the  opinion  of  the  writer  it  is  catabolized  within  the  cells,  largely  in  the 
liver,  possibly  in  the  muscles.  All  opinions  are  more  or  less  hypothetical ; 
the  following,  however,  seem  to  the  author  to  follow  the  line  of  least 
resistance. 

It  is  assumed  that  an  equilibrium  exists  between  the  cells  of  the 
body  and  the  concentration  of  protein  in  the  blood  plasma.  There  is 
a  certain  minimum  protein  concentration  of  the  blood  plasma;  if  this 
be  reduced,  indifferent  cells  yield  their  protein  to  form  blood  protein 
for  the  maintenance  of  this  minimal  concentration.  If  by  forced  feed- 
ing the  maximum  concentration  of  blood  protein  be  exceeded,  the 
excess  is  thrown  upon  the  cells,  in  the  form  of  inclusions  within  the 
cells.  The  high  protein  concentration  of  the  blood  plasma  and  the 
inclusions  of  protein  within  the  cells,  in  accordance  with  the  law  of 
mass  action,  result  in  the  acceleration  of  the  catabolism  of  this  excess 
of  protein  by  the  cells,  the  reaction  continuing  until  all  the  excess  has 
been  catabolized,  and  the  protein  concentration  of  the  cells  and  blood 
returned  to  the  normal. 

When  an  animal  is  given  excessive  rations  of  protein,  as  a  rule  the 
nitrogen  of  the  excess  is  promptly  eliminated  in  the  urine.  The  adult 
body,  in  health  and  full  nutrition,  tolerates  the  deposition  of  fat  and 
glycogen,  but  does  not  tolerate  the  deposition  or  storage  of  protein, 
for  which  fact  the  above  explanation  has  been  advanced.  If  the  feed- 
ing be  very  forced,  a  portion  of  the  nitrogen  is  retained.  Assuming 
that  this  retention  is  in  the  state  of  protein  and  not  a  retention  (a  non- 
elimination)  of  the  products  of  catabolism,  this  we  explain  as  due  to 
an  increase  in  the  concentration  of  protein  in  the  blood  and  to  inclu- 


.">NS  THE  METABOLISM  OF  PROTEIN 

sions  of  protein  in  the  cells,  the  cellular  capacities  for  the  catabolism 
of  protein  being  exceeded.  When  the  forced  feeding  is  suspended,  the 
retained  protein  is  catabolized  within  the  following  few  days,  and 
the  relations  return  to  the  normal.  The  capacity  for  such  retentions 
varies  with  different  animals  and  with  different  individuals  and  at 
different  ages.  In  youth  retention  means,  in  part  at  least,  growth, 
a  true  fleshening.  And  youth  extends,  so  far  as  the  growth  of  muscle 
is  concerned,  up  to  some  twenty-four  years.  Following  periods  of 
subnutrition  or  illness,  retentions  occur  that  indicate  restitution.  But 
with  some  normal  adult  individuals  a  certain  degree  of  retention  occurs 
that  apparently  represents  a  toleration  of  the  cells  or  a  true  increase 
in  the  protoplasm  of  the  cells.  The  coefficient  of  protoplasm  we  are 
inclined  to  hold  rather  invariable;  and  yet  it  is  possible  that  in  some 
individuals  at  least  the  body  cells,  especially  the  muscle  cells,  may 
exhibit  a  tendency  to  variations,  and  may  increase  or  decrease  their 
protoplasm  within  certain  limits  depending  upon  the  states  of  nutrition. 
But,  all  in  all,  the  distinction  between  the  states  of  endogenous  protein 
and  the  exogenous  protein  is  fundamental. 

In  the  qualitative  sense  the  catabolisms  of  endogenous  and  exogenous 
protein  are  different.  The  catabolism  of  exogenous  protein  leads 
only  to  urea  and  ammonia,  possibly  to  a  small  rest  of  amino-acids. 
The  catabolism  of  the  protoplasmic  protein  leads  to  more  specific 
products.  Some  urea  is  produced,  possibly  only  in  the  glandular 
organs.  But  creatinin  is  the  end  product  of  the  catabolism  of  the 
protoplasm  of  the  muscle  cells;  and  it  is  probable  that  it  alone,  and  not 
urea  or  ammonia,  is  here  produced.  The  nucleic  acid,  derived  from  the 
endogenous  protein  by  synthesis,  yields  purin  bases  and  uric  acid.  It 
has  been  suggested  that  the  strictly  endogenous  protoplasmic  catab- 
olism might  yield  no  urea,  which  would  therefore  be  referable  to  the 
exogenous  protein  alone.  This  idea  is  not  to  be  entertained;  urea 
is  one  of  the  end  products  of  the  catabolism  of  protoplasmic  protein, 
possibly  only  of  the  glandular  organs.  The  elimination  of  urea  under 
conditions  of  nitrogen  starvation  with  full  carbon  nutrition,  where  no 
protein  is  burned  as  fuel,  indicates  that  urea  is  one  of  the  end  products 
of  endogenous  protein  catabolism.  This  fraction  of  urea  is  very  small, 
corresponding  to  not  over  2  grams  of  nitrogen  per  day.  With  this 
small  figure  we  must  contrast  the  15  or  even  20  grams  of  urea  nitrogen 
observed  in  the  urine  of  heavy  eaters  of  protein.  This  excess  of  protein 
the  body  rejects;  it  is  hydrolyzed,  and  the  nitrogen  eliminated  as  urea. 
This  process  of  disintegration  is,  of  course,  not  a  total  loss  to  the 
body,  since  the  fatty  acids  are  either  burned  or  converted  into  sugar; 
but,  as  will  be  pointed  out  later,  it  is  a  very  uneconomical  method  of 
obtaining  sugar. 

While  it  is  true  that  the  intracellular  proteolytic  ferment  must  be 
credited  with  the  power  of  hydrolyzing  protein  to  the  final  amino- 
acids,  it  is  at  the  same  time  certain  that  this  is  not  fully  accomplished. 
The   urine   contains   normally   a  substance   termed   oxyproteic   acid, 


THE  CATABOLISM  OF  PROTEIN  389 

together  with  several  derivatives  thereof.  This  is  a  polypeptid  which 
may  be  isolated  and  yields  on  acid  hydrolysis  glycocoll,  alanin,  phenyl- 
alanin,  leucin,  glutamic,  and  possibly  aspartic  acid.  In  addition  to 
these,  the  substance  contains  sulphur;  and  although  cystin  has  not 
been  isolated,  it  may  be  assumed  that  the  sulphur  is  present  in  the  state 
of  cystin.  A  goodly  fraction  of  the  rest-nitrogen  and  the  neutral  sulphur 
of  the  urine  are  contained  in  this  body  and  its  derivatives.  Its  presence 
in  the  urine  might,  on  the  one  hand,  be  regarded  as  an  incidental 
elimination,  a  slipping  through  the  kidney  before  cleavage  could  be 
completed.  On  the  other  hand,  it  might  be  derived  from  some  special 
protein  in  which  these  amino-acids  were  so  combined  as  to  form  a  group 
resistant  to  the  action  of  the  endotrypsin.  It  is  not  known  that  the 
amount  of  the  substances  exhibits  any  variations  in  disease,  though  could 
such  be  determined,  light  might  be  thrown  on  the  ultimate  source. 

There  are  known  variations  in  the  elimination  of  the  rest-nitrogen 
(retentions) ;  but  we  haxe  no  knowledge  of  variations  in  the  amount 
formed  in  metabolism  under  different  conditions.  Certainly  it  is  not  a 
variable  of  the  total. 

In  connection  with  severe  infections,  internal  suppurations  and 
sometimes  in  subjects  with  advanced  leukemia  or  malignant  neoplasms, 
peptone  or  proteose  is  eliminated  in  the  urine.  Whether  these  represent 
incompletely  hydrolyzed  protein  of  the  protein  catabolism  or  are  the 
result  of  abnormal  enzyme  reactions  on  the  part  of  the  infections,  is 
not  clear.  They  are  usually  not  accompanied  by  an  excess  of  amino- 
acids  in  the  urine.  Foreign  peptone  is  highly  toxic;  but  in  these  cases 
it  is  not  possible  to  separate  the  symptoms  of  the  disease  from  such 
as  may  have  been  caused  by  the  peptone. 

As  stated,  the  aseptic  postmortem  autolysis  of  organs  represents  ap- 
parently en  bloc  what  occurs  in  individual  cells  following  their  death. 
The  cause  of  the  hydrolysis  is  to  be  attributed  to  intracellular  proteolytic 
ferment  present  in  the  cells  at  the  time  of  the  removal  of  the  organ  from 
the  body,  which  continues  to  be  active  and  digests  the  cells  them- 
selves. In  certain  conditions  of  disease  we  observe  digestions  that 
are  in  every  apparent  respect  identical  with  this  postmortem  autolysis. 
Thus  in  the  resolution  of  croupous  pneumonia,  in  the  liquefaction  of 
exudates,  in  the  inspissations  of  hemorrhages,  in  the  liquefaction 
necrosis  of  neoplasms,  and  in  the  involution  of  the  uterus  after  labor 
we  have  conditions  that  are  in  all  probability  comparable  to  post- 
mortem autolysis.  If  one  could  deprive  an  area  of  the  liver  of  its 
circulation,  it  is  certain  that  the  liver  tissue  within  this  area  would  be 
digested  just  as  is  the  liver  tissue  in  postmortem  autolysis,  though 
with  a  difference  of  velocity.  In  tuberculosis  large  masses  of  exudate 
are  sometimes  accumulated  and  these  do  not  liquefy  in  the  same  manner 
as  the  tissues  above  named.  Direct  experimentation  with  the  cheesy 
material  of  tuberculosis  has  shown  that  it  is  not  digestible  by  ferments 
of  the  trypsin  type;  and  with  this  finding  the  resistant  behavior  of 
tuberculous  exudations  in  disease  is  explained. 


390  THE  METABOLISM  OF  PROTEIN 

The  Formation  of  Glucose  from  Amino-acids. — That  glucose  is  formed 
in  the  body  from  protein  has  been  established  by  three  experimental 
facts.  If  a  dog,  freed  of  glycogen  by  starvation,  be  fed  with  a  carbo- 
hydrate-free protein,  like  casein  or  codfish  flesh,  and  the  eliminations 
of  nitrogen  and  carbon  checked  up  against  the  inputs,  it  will  be  found 
that  there  has  been  a  notable  retention  of  carbon  in  the  body,  if  the 
protein  input  was  liberal  and  the  animal  was  not  worked.  This  carbon 
could  scarcely  have  been  retained  in  any  other  form  than  sugar  or  fat. 
Since  there  is  no  evidence  that  fat  can  be  formed  from  protein  except 
via  sugar,  the  fat  may  be  disregarded.  Analyses  of  the  tissues  of  such 
a  dog  will  show  rich  deposits  of  glycogen,  of  which  the  tissues  were 
previously  freed  by  work  and  starvation.  Unless  the  glycogen  and 
sugar  were  derived  from  fat,  they  must  have  been  derived  from  protein. 

A  dog  with  pancreatic  diabetes,  if  carefully  maintained,  will  eliminate 
an  amount  of  sugar  in  such  excess  of  the  possibly  carbohydrate  content 
of  the  body  and  the  diet  as  to  make  certain  a  derivation  of  sugar  from 
protein,  unless  again  it  could  have  proceeded  from  fat. 

A  dog  with  phloridzin  intoxication,  freed  of  glycogen  by  work  and 
starvation,  and  fed  on  carbohydrate-free  protein  (or  predigested  protein) 
will  eliminate  amounts  of  glucose  that  are  far  in  excess  of  any  possible 
storage  of  carbohydrate  in  the  body  of  the  animal.  This  glucose  must 
have  come  from  protein,  unless  it  could  have  been  formed  from  the 
fats.  In  all  three  experiments,  it  is  clear  that  derivation  from  the  fat 
is  not  chemically  or  experimentally  excluded.  But  in  the  absence  of  any 
direct  proof  of  the  origin  of  glucose  from  fat,  and  in  the  possession 
of  direct  proof  that  amino-acids  can  be  converted  into  sugar,  we  will 
regard  it  as  established  that  in  these  experiments  sugar  is  formed  from 
protein.  No  interpretation  will  hold  for  all  three  experiments  unless 
it  regards  this  formation  of  glucose  from  protein  as  a  physiological 
process,  not  an  artificial  adaptation  or  a  pathological  variation.  We 
will,  therefore,  regard  it  as  established  that  in  the  normal  metabolism 
of  the  body,  glucose  is  formed  from  protein. 

Direct  experiments  having  shown  that  glucose  can  be  formed  from 
amino-acids,  for  the  present  certainly  we  must  regard  this  as  the  only 
modus  for  the  derivation  of  glucose  from  protein.  There  was  once 
much  said  of  the  nitrogenous  moiety  and  the  carbohydrate  moiety  of 
the  protein  molecule;  there  is  no  such  thing,  there  are  only  collections 
of  amino-acids  in  protein.  It  cannot  be  maintained  in  advance  that 
glucose  can  be  formed  from  all  amino-acids.  Each  amino-acid  resident 
in  protein  must  be  tested,  and  for  each  amino-acid  the  demonstration 
must  be  exacted.  For  the  present  there  is  from  this  point  of  view  no 
way  of  stating  how  much  sugar  can  be  formed  from  the  products  of 
the  catabolism  of  a   unit  protein. 

How  are  we  to  picture  this  formation  of  sugar  from  amino-acids? 
The  most  natural  point  of  view,  possibly,  would  be  to  assume  first 
a  reaction  of  deaminization,  whereby  the  NH2  group  or  groups  would 
be  split   off,  following  which   the  body  would  form  sugar  from  the 


THE  CATABOLISM  OF  PROTEIN  391 

hydroxyl-fatty  acid.  But  at  once  an  obvious  question  arises.  Does 
the  body  form  sugar  from  these  derivatives  of  fatty  acids  when  they  are 
introduced  into  the  body  ?  For  illustration,  glycocoll  is  known  in  experi- 
ment to  be  a  sugar  builder.  Glycocoll  is  amino-acetic  acid,  and  when 
the  NH2  group  is  split  off,  it  would  leave  glycolic  acid,  CH2OH.COOH. 
But  does  the  body  form  sugar  of  glycolic  acid  when  it  is  administered? 
Administered  to  rabbits,  glycolic  acid  is  converted,  in  part  at  least,  into 
oxalic  acid.  It  is  clear  that  from  the  simple  fatty  acids  no  sugar  can  be 
formed.  But  we  have  evidence  that  from  the  alpha  hydroxy  1 -acids  glucose 
may  be  formed.  The  relation  is  best  seen  in  the  case  of  propionic  acid. 
This  fatty  acid  is  burned  directly  in  the  organism;  but  its  alpha  hydroxyl- 
acid,  lactic  acid,  is  convertible  under  favorable  conditions  of  concentra- 
tion into  glucose.  If  the  deaminization  of  the  amino-acid  occurs 
directly  the  trend  of  the  reaction  would,  therefore,  be  in  the  direction 
of  sugar.  But  for  some  amino-acids,  as  for  phenylalanin,  it  is  believed 
that  the  corresponding  simple  fatty  acid  is  produced,  and  this  is 
not  favorable  to  the  formation  of  sugar,  since  these  simple  fatty  acids 
are  burned  directly  in  the  body.  An  illustration  will  make  the  point 
clear.  Viewing  deaminization  as  a  direct  reaction  with  the  addition 
of  water  we  would  have  for  alanin: 

Alanin  Lactic  acid  Propionic  acid 

CH3  CH3  CH3 

CHNH2   +  H20  =  CHOH    +  NH3    CH2 
COOH  COOH  COOH 

Now  phenylalanin  is  known  on  bacterial  deaminization  to  form  not 
lactic  acid  but  propionic  acid;  which  in  turn  becomes  phenylacetic 
acid,  following  which  the  fatty  acid  is  completely  burned,  the  aromatic 
ring  being  converted  into  benzoic  acid,  phenol  or  cresol,  or  burned. 


Phenylanin 

Phenylpropionic  acid 

Phenylacetic  acid 

CH 
HC        CH 

CH 

/\ 
HC        CH 

CH 
HC        CH 

HC        CH 
C.CH2 

HC        CH 
C.CH2 
CH2 
COOH 

HC        CH 
C.CH2 
COOH 

CHNH2 
COOH 

Possibly  it  is  the  presence  of  the  phenyl  group  that  makes  the  difference 
in  the  results  of  the  reaction  of  deaminization. 

Unless  we  can  believe  that  the  deaminizations  take  the  course  depicted 
above  for  alanin,  it  would  be  much  more  logical  to  assume  that  the 
amino-acids  are  first  converted  into  amino  sugars  and  these  then  deami- 
nated.     The  composition  of  lysin  and  its  resemblance  to  glucosamin 


392 


THE  METABOLISM  OF  PROTEIN 


gives  the  clue  to  what  may  be  regarded  in  some  instances  as  the  correct 
interpretation.    The  equations  will  make  the  point  clear. 


Glucose 

CHO 
CHOH 

CHOH 

I 
CHOH 

CHOH 

CH2OH 


Glucosamin 

CHO 
CHOH 
CHOH 
CHOH 

CHNH2 

I     . 
CH2OH 


Lysin 

CH2NH2 

CH2 

CH2 

CH2 

CHNH2 

COOH 


The  amino-acid  is  converted  into  the  amino  sugar.    Lysin  has  not  been 
tested  for  its  sugar  building  powers. 

Close  relations  exist  also  between  alanin  and  its  derivatives 
glycerose  and  lactic  acid. 


and 


Glycerose 

COH 

CHOH 

CH2OH 


Glyceric  acid 

COOH 

CHOH 

I 
CH2OH 


Alanin 
CH3 

CHNH2 

I 
COOH 


Serin 

CH2OH 
CHNH2 
COOH 


Lactic  acid 

CH3 

I 

CHOH 
COOH 


Serin  is  obviously  an  amino-glyceric  acid.  Alanin  has  been  tested 
directly  on  the  depancreatized  dog  and  found  to  yield  glucose.  We  are 
justified  in  assuming  that  the  amino-acid  derived  from  alanin  (serin) 
will  react  as  does  alanin.  For  histidin,  phenylalanin,  and  tryptophan 
on  the  other  hand  (they  have  not  been  tested),  the  same  could  hardly 
be  true.  It  seems  quite  certain  that  tyrosin,  phenylalanin,  and  trypto- 
phan do  not  yield  their  fatty  acid  for  the  synthesis  of  glucose.  Never- 
theless, recent  investigations  suggest  that  histidin,  true  to  its  lactic 
acid,  yields  glucose  in  the  body,  in  part  at  least  or  under  certain  circum- 
stances; and  possibly  future  studies  may  reverse  the  present  opinion 
for  tyrosin,  phenylalanin,  and  tryptophan.  Here  we  now  believe  occurs 
deaminization  with  a  later  combustion  of  the  fatty  acids.  This  has  been 
made  fairly  clear  by  our  knowledge  of  the  catabolism  of  the  phenyl- 
amino-acids  as  revealed  in  alcaptonuria.  It  is  fairly  certain  that 
cystin  is  not  a  source  of  glucose.  Aspartic  acid  gives  positive  results, 
glutamic  acid  also.  Glutamic  acid  could  become  converted  into  glyceric 
acid  by  oxidation  at  the  beta  carbon,  when  it  would  split  into  one 
molecule  each  of  glyceric  acid  and  acetic  acid. 


COOH 
CH2 

CH2 

+     2H20 
CHNH2 

COOH 


COOH 
I 
CH3     ' 


CH2OH 

I 
CHOH 

COOH 


+     NH3 


THE  CATABOLISM  OF  PROTEIN  393 

Of  glycocoll  it  is  positively  known  that  sugar  is  formed  from  it,  though 
the  chemical  relations  to  sugar,  as  stated,  are  less  obvious.  It  may, 
however,  be  converted  into  glycolic  acid,  this  then  reduced  to  glycol- 
aldehyd,  which  can  be  condensed  to  form  glucose. 

CH2NH2  CH2OH 

I  +     H20  =     7 

COOH  COOH  +     NH3 

CH2OH  CH2OH 

COOH  COH 

3CH2OH.COH   =  CHO.CHOH.CHOH.CHOH.CHOH.CH2OH 

For  leucin  a  positive  demonstration  could  not  be  accomplished. 
We  would  not  expect  ornithin  to  yield  sugar.  Prolin  we  may  exclude. 
Much  more  extensive  investigations  of  the  sugar-building  properties 
of  the  different  amino-acids  are  necessary  before  the  subject  can  be 
considered  as  clarified;  the  opinions  expressed  represent  the  present 
state  of  information.  From  this  all  it  is  clear  also  that  we  are  not 
in  a  position  to  decide  whether  the  NH2  group  is  split  off  preparatory 
to  the  formation  of  sugar  or  later  split  off  from  the  amino  sugar. 

Taking  together  experimental  work  and  considerations  bearing  on 
constitution,  we  may  tabulate  the  probable  relations  of  the  different 
amino-acids  to  the  formation  of  sugar  as  follows: 

Sugar  builders  Not  sugar  builders  Unplaced 

Glycocoll.  Tyrosin.  Leucin  (?). 

Alanin.  Phenylalanin.  Valin. 

Serin.  Tryptophan. 

Aspartic  acid.  Histidin. 

Glutamic  acid.  Pyrrol. 

Lysin.  Arginin. 
Cystin. 

Glycocoll  becomes  glucose  via  glycolaldehyd ;  alanin,  serin,  aspartic 
and  glutamic  acids  pass  into  glucose  via  lactic  acid  (glycerose);  lysin 
either  passes  directly  through  the  corresponding  amino  sugar  or  might 
be  split  into  two  molecules  of  lactic  acid  or  glycerose. 

Very  interesting  are  the  time  relations  of  this  process.  In  the  phlorid- 
zinized  dog,  it  is  assumed  that  no  sugar  is  burned  and  that  neither  sugar 
nor  nitrogen  is  stored.  The  appearance  of  the  sugar  and  nitrogen 
in  the  urine  of  such  a  dog  after  the  administration  of  a  known  ration 
of  protein  may  be  taken  as  an  indication  of  the  relative  velocities  in 
the  two  reactions.  When  the  urine  is  collected  in  short  periods,  it  is 
found  that  the  marked  elimination  of  glucose  begins  first,  and  reaches 
the  top  of  its  wave  some  three  to  five  hours  before  the  elimination  of 
the  nitrogen  reached  the  crest  of  its  wave.  The  eliminations  begin 
about  the  same  time,  and  are  completed  at  about  the  same  time.  But 
the  curves  are  reversed.    The  curve  of  sugar  output  rises  rapidly  and 


394  THE  METABOLISM  OF  PROTEIN 

recedes  slowly;  the  curve  of  nitrogen  output  rises  slowly  and  descends 
rapidly.  That  this  difference  is  wholly  metabolic  and  in  nowise  secretory 
is  not  fully  established. 

From  this  point  of  view  we  cannot  attempt  to  make  an  estimate 
of  the  amount  of  glucose  that  the  body  derives  from  protein  in  the 
diet,  partly  because  there  are  no  studies  on  diets  of  known  amino- 
acid  composition,  and  partly  because  the  question  is  not  settled  for 
all  the  amino-acids.  Such  a  study  indeed  could  not  today  be  carried 
out  for  the  simple  reason  that  we  do  not  know  accurately  the  quantita- 
tive content  of  the  several  amino-acids  in  a  single  protein;  in  no  case 
(on  account  of  defects  in  the  methods),  do  the  figures  for  the  isolated 
amino-acids  check  up  to  anywhere  near  the  original  weight  of  the 
protein  under  investigation.  We  simply  know  that  glucose  is  formed 
from  protein,  and  we  regard  this  process  as  the  result  of  the  conversion 
of  the  amino-acids  into  sugar.  An  idea  of  how  much  glucose  can  be 
formed  may,  however,  be  obtained  in  an  indirect  manner.  If  we  assume 
that  in  a  dog  with  complete  phloridzin  intoxication  no  sugar  is  burned 
but  instead  all  is  swept  out;  if  we  assume  in  a  dog  with  pancreatic 
diabetes  that  the  power  of  burning  glucose  is  lost  and  that,  therefore, 
all  the  sugar  formed  in  the  body  is  eliminated  in  the  urine — then  in 
an  experiment  extending  through  many  days  on  a  diet  free  of  carbo- 
hydrate, we  may  from  the  ratio  of  glucose  to  nitrogen  in  the  urine 
calculate  the  amount  of  sugar  formed.  The  assumption  that  in  these 
two  experiments  no  sugar  is  being  burned  is  not  founded;  some  sugar 
is  burned,  though  probably  not  much,  and  the  real  ratio  is,  therefore, 
higher  than  the  ratio  obtained.  In  the  discussion  of  the  glucose :  nitrogen 
ratio  in  diabetes  this  was  set  at  5  :  1  as  a  maximum,  in  order  to  create 
no  prejudice  in  the  discussion  of  the  possible  origin  of  sugar  from  fat. 
As  a  matter  of  fact,  that  ratio  is  too  high.  One  obtains  it  during  the 
first  days  of  a  phloridzin  glucosuria,  but  it  is  there  the  expression  of 
a  washing-out  of  stored  sugar,  or  of  a  later  rise  in  N  output.  Later 
the  ratio  sinks  to  about  3.7  :  1,  never  over  4:1.  While  in  human 
diabetes,  where  the  conditions  are  difficult  of  control,  high  ratios  are 
sometimes  seen,  in  the  pancreatic  diabetes  of  the  dog  it  is  rare  to  find 
a  ratio  over  3:1,  usually  about  2.7  :  1.  But  as  stated,  on  account 
of  slight  combustion  of  sugar,  the  real  ratio  is  somewhat  higher.  In 
all  discussions  of  the  G  :  N  ratio  with  ingested  protein  and  tissue 
protein,  it  must  be  borne  in  mind  that  it  is  possible  that  the  body  forms 
more  glucose  from  a  unit  of  food  protein  than  from  tissue  protein. 

Now  when  an  animal  forms  from  protein  3.7  parts  of  glucose  for 
each  part  of  nitrogen,  obviously  this  is  less  than  half  the  amount  of 
glucose  that  corresponds  to  the  total  carbon  content  of  protein.  If 
all  the  carbon  in  a  molecule  of  protein  were  converted  into  glucose 
this  would  amount  to  1.3  gram,  a  ratio  to  the  nitrogen  in  the  gram  of 
protein  of  8  :  1.  If  we  first  subtract  the  carbon  that  will  later  combine 
with  the  NH2  to  form  urea,  the  ratio  will  be  reduced  to  7  :  1.  The 
deaminization  of  the  amino-acids  or  amino  sugars  leaves  fatty  acids 


THE  CATABOLISM  OF  PROTEIN  395 

and  sugars;  the  free  NH3  will  at  once  combine  with  C02  of  the  tissue 
fluids  to  form  ammonium  carbonate.  In  other  words,  the  NH2  groups 
(except  in  the  case  of  arginin)  do  not  form  urea  with  any  of  the  carbon 
of  the  molecules  of  amino-acids  from  which  they  were  split  off.  There- 
fore, all  the  carbon  in  the  fatty  acids  or  sugars  must  be  regarded  as 
available  for  the  synthesis  of  glucose,  so  far  as  the  NH2  groups  are 
concerned,  and  a  subtraction  is  not  correct.  The  ratio  theoretically 
is,  therefore,  8:1;  the  actual  ratio  is  less  than  4  :  1,  let  us  say  3.7  :  1. 
Does  this  represent  the  sugar-forming  power  of  protein?  May  we 
infer  from  this  that  less  than  one-half  of  the  amino-acids  in  the  molecule 
of  protein  is  convertible  into  sugar?  (As  elsewhere  stated,  if  the 
amino-acids  form  glucose  only  in  proportion  to  their  possible  conver- 
sion into  lactic  acid,  from  a  gram  of  casein  about  0.58  gram  of  glucose 
could  be  derived,  a  ratio  of  about  3.5  : 1.)  The  amount  that  is  burned, 
under  the  conditions  of  the  experiment  may  be  much  higher  than 
supposed,  though  the  respiratory  quotient  does  not  lead  to  such  an 
opinion.  The  nitrogen  cannot  be  retained  in  the  body  in  a  prolonged 
experiment,  unless  the  input  be  very  excessive.  There  is  evidence 
that  when  a  starying  phloridzinized  animal  catabolizes  his  own  protein, 
there  is  a  better  utilization  (less  sugar  is  formed)  than  when  subsisting 
on  diet  protein.  There  is  also  evidence  that,  within  narrow  limits,  the 
nearer  the  protein  input  is  to  the  known  minimal,  the  less  sugar  relatively 
is  formed  from  it.  With  increases  of  protein  input,  the  ratio,  however, 
remains  the  same;  doubling  the  protein  doubles  the  sugar  and  the 
nitrogen,  the  ratio  remaining  constant.  No  such  proportionality  is 
to  be  seen  in  diabetes  in  man,  however.  It  is  in  fact  partly  the  differ- 
ences in  the  results  in  animals  and  in  man  that  make  one  cautious  in 
defining  the  sugar  formation  from  protein  on  the  basis  of  the  glucose : 
nitrogen  ratio.  That  a  fraction  of  the  fatty  acids  of  protein  is  burned 
directly  cannot  be  doubted.  With  all  the  data,  therefore,  one  cannot 
yet  state  that  the  ratio  of  3.7  :  1  represents  definitely  the  proportion  of 
carbon  that  in  the  catabolism  of  protein  passes  into  sugar.  And  this 
without  consideration  of  the  question  of  the  origin  of  sugar  from  fat. 

The  conversion  of  the  amino-acids  into  glucose  is  assumed  to  occur 
in  the  liver  exclusively,  though  for  this  limitation  no  decisive  reason 
can  be  offered. 

The  Deaminization  of  the  Amino-acids. — This  we  believe  occurs  in 
the  state  of  amino-acids  for  such  of  these  as  are  to  be  burned  directly; 
for  such  as  are  to  be  converted  into  sugar,  the  NH2  might  be  split  off 
before  or  after  the  state  of  amino  sugar,  as  previously  explained.  Many 
tissues,  liver,  spleen,  and  kidneys,  contain  deaminization  ferments. 
The  reactions  are  of  common  type,  illustrated  for  alanin: 

Alanin  Lactic  acid 

CH3  CH3 

I  I 

CHNH2    +  H20   =   CHOH     +  NH3 
COOH  COOH 


396 


THE  METABOLISM  OF  PROTEIN 


The  ammonia  combines  with  the  carbon  dioxid  of  the  fluids  to  form 
ammonium  carbonate,  the  parent  substance  of  urea.  Lactic  acid  would 
be  converted  into  sugar.  In  the  case  of  glycocoll,  the  lower  sugar  would 
be  condensed  to  form  glucose. 

A  special  form  of  deaminization  ferment  is  arginase,  found  in  the  liver. 
It  splits  arginin  to  form  one  molecule  of  urea  and  one  of  ornithin. 


Arginin 

NH 

C— NH2 

NH 

CH2 

CH2 

CH2 

CHNH2 

COOH 


Urea 


+ 


H20 


NH2 

do 

\ 

NH2 


+ 


Ornithin 


CH2NH2 

CH2 

CH2 
I 
CHNH2 

COOH 


The  ornithin  is  then  deaminated  like  the  other  amino-acids. 

Normal  human  urine  contains  but  one  defined  amino-acid,  glycocoll; 
present,  however,  are  traces  of  other  amino  nitrogen.  If  large  amounts 
of  amino-acids  are  introduced  into  the  circulation  of  an  animal,  a  frac- 
tion will  be  eliminated.  In  certain  severe  organic  diseases  of  the  liver, 
as  acute  yellow  atrophy,  chloroform  necrosis,  phosphorus  poisoning, 
eclampsia,  and  occasionally  in  severe  infections  and  in  diabetic  coma 
different  amino-acids  appear  in  the  urine,  leucin,  tyrosin,  and  cystin 
being  the  most  prominent.  Their  presence  must  be  regarded  as  due 
to  the  failure  of  the  deaminization  reaction.  And  the  presence  of 
amino-acids  in  the  urine  in  especial  connection  with  diseases  of  the 
liver  of  acute  necrotic  type,  leads  to  the  inference  that  it  is  largely  in 
the  liver  that  the  deaminizations  of  the  protein  catabolism  occur. 
It  is  in  phosphorus  poisoning  also  that  large  amounts  of  lactic  acid 
are  eliminated  in  the  urine.  This  might  obviously  have  come  in  part 
from  the  amino-acids  of  the  alanin  type.  Apparently  the  liver  fails 
in  part  in  the  deaminizations,  and  at  the  same  time  is  not  able  to 
utilize  the  lactic  acid. 

Oxidation  of  the  Products  of  Protein  Catabolism. — It  is  in  the  oxida- 
tions that  most  of  the  energy  of  the  proteins  is  set  free  as  heat  or  made 
available  as  work.  In  the  reactions  of  hydrolysis  and  deaminization 
we  deal  with  practically  isothermic  reactions;  there  is  heat  set  free 
but  the  amount  is  small.  The  heat  values  lie  largely  in  the  sugar  and 
fatty  acids,  since  the  combining  of  the  NH3  with  the  C02  it  meets  in 
the  circulating  fluids  is  practically  an  isothermic  reaction.  If  all  the 
carbon  in  a  molecule  of  protein  (52  per  cent.)  were  converted  into 
glucose,  this  would  yield  about  1 .3  gram,  of  a  heat  value  of  4.5  Calories, 


THE  GATABOLISM  OF  PROTEIN  397 

against  a  heat  value  in  the  original  protein  of  possibly  4.3  Calories. 
These  are  rounded  figures  and  may  be  regarded  as  equal.  The  total 
caloric  value  of  the  same  protein  in  a  calorimeter  is  about  5.7  Cal. 
When  from  this  is  subtracted  the  heat  set  free  in  the  oxidation  of  the 
two  hydrogens  of  urea  (about  1  Cal.  for  the  urea  of  1  gram),  the  small 
amount  of  heat  evolved  in  the  reactions  of  hydrolysis  and  deaminization 
becomes  apparent.  This  calculation  would  not  hold  if  but  half  of  the 
carbon  of  the  molecule  of  protein  were  converted  into  glucose  (which 
apparently  approximates  the  truth),  since  we  do  not  know  the  heat 
value  of  the  fatty  acids  that  are  burned  directly. 

One  reads  so  much  in  the  older  literature  of  the  nitrogenous  and 
the  non-nitrogenous  fractions  of  the  molecule  of  protein  that  it  is  neces- 
sary to  insist  on  the  radical  change  in  our  conception  of  the  catabolism 
of  the  molecule  of  protein  introduced  by  our  present  idea  of  hydrolysis 
to  amino-acids  and  deaminization  of  the  latter.  Whether  the  oxy- 
fatty  acids  thus  set  free  are  converted  into  sugar  or  burned  directly, 
whether  the  formation  of  sugar  occurs  from  the  oxy-fatty  acid  or  from 
the  amino-acids,  the  fact  remains  that  following  the  reaction  of  deami- 
nization the  nitrogenous  portion  is  subject  to  no  further  oxidations 
and  is  not  a  carrier  of  energy  for  the  animal  body.  The  ammonia 
set  free  in  the  reaction  of  deaminization  meets  in  the  circulating  fluids 
the  carbon  dioxid  set  free  in  the  combustion  of  fat  and  sugar.  These 
combine  to  form  ammonium  carbonate,  which  through  the  inter- 
mediary stage  of  ammonium  carbamate  is  converted  into  urea.    Thus : 

2NH3  O.NH4  O.NH4  NH2 

+  =         c=o  =      c=o  =      c=o 

\  \  \ 

H2COs  O.NH4  NH2  NH2 

This  is  not  an  oxidation;  ammonium  carbonate  contains  50  per 
cent,  of  oxygen,  and  urea  only  26  per  cent.  It  is,  therefore,  not  per- 
missible to  speak  of  the  oxidation  of  the  "nitrogenous  moiety"  of  the 
protein  molecule;  the  "non-nitrogenous  moiety"  (the  fatty  acids  and 
glucose  derived  from  them  in  part)  alone  are  available  for  reactions 
of  oxidation.  Under  these  circumstances  the  terms  nitrogenous  and 
non-nitrogenous  moiety  were  best  abandoned,  since  the  cleavage  of 
the  molecule  of  protein  is  into  amino-acids  and  not  into  two  such 
fractions  at  all,  and  the  amino-acids  are  then  split  through  deaminiza- 
tion into  ammonia  and  oxy-fatty  acids. 

The  mechanism  of  the  oxidation  of  the  glucose  has  been  discussed 
under  the  carbohydrate  metabolism.  The  combustion  of  the  fatty 
acids  we  regard  as  a  direct  building  down  to  acetic  and  formic  acid, 
with  the  final  formation  of  water  and  carbon  dioxid.  These  reactions 
we  attribute  to  the  influence  of  oxidation  ferments.  The  experimental 
work  on  the  oxidation  ferments  in  animal  and  plant  tissues  is  at  the 
present  time  in  a  state  of  apparently  inextricable  confusion.      The 


398  THE  METABOLISM  OF  PROTEIN 

domains  of  the  catalases,  the  oxidases  and  the  peroxidases  are  peopled 
with  contradictions.  Oxidations  occur  apparently  in  all  tissues  and  in 
the  circulating  fluids.    Beyond  this  we  actually  know  nothing. 

The  Formation  of  Urea. — Urea  is  the  chemical  state  in  which  the  largest 
part  of  the  NH2  of  the  amino-acids  of  protein  in  mammals  is  eliminated. 
In  birds  and  reptiles  the  trend  of  the  reaction  is  not  in  the  direction 
of  urea;  uric  acid  represents  the  chief  end  product.  In  amphibia  and 
most  aquatic  animals,  however,  urea  is  again  the  end  product.  There 
are  but  two  known  and  proved  reactions  whereby  urea  is  formed  from 
amino-acid  in  the  body  of  the  higher  animals.  And  so  far  as  our  knowl- 
edge extends,  the  formation  of  urea  from  amino-acids  is  thus  adequately 
and  fully  explained,  and  there  is  no  reason  or  purpose  in  invoking  the 
many  possible  laboratory  reactions  for  the  formation  of  urea. 

The  first  of  these  (though  discovered  last,  stated  first  because  it 
involves  but  a  small  fraction  and  required  no  discussion),  is  the  forma- 
tion of  urea  from  arginin  by  direct  cleavage  through  the  action  of 
arginase  in  the  liver.     The  reaction  is  made  clear  in  the  equation: 

Arginin  +  water  =  ornithin  +         urea 

NH2  NH2 

I  / 

HN  =  C— NH  C=0 

I  \ 

CH2  CH2NH2  NH2 

I  '  + 

CH2  CH2 

CH2  +     H20      =     CH2 

CHNH2  CHNH2 

COOH  COOH 

The  parenteral  introduction  of  arginin  is  followed  promptly  by  increase 
in  the  elimination  of  urea  corresponding  to  half  the  nitrogen  of  the 
arginin  given.  Since  arginin  does  not  at  the  most  represent  over  10 
per  cent,  of  the  amino-acids  of  mixed  proteins,  the  portion  of  urea  thus 
derived  is  but  a  small  fraction  of  the  total.  But  the  reactio'n  and  its 
acceleration  by  a  special  ferment  that  operates  so  far  as  known  largely 
in  one  organ,  makes  the  process  of  particular  interest  and  instruction. 
.The  NH2  groups  from  the  larger  fraction  of  the  other  amino-acids 
(and  including  the  ornithin),  with  certain  exceptions  that  are  later  to 
be  pointed  out,  are  split  off  by  deaminization  ferments;  in  the  case  of 
such  amino-acids  as  are  destined  to  sugar  formation  either  before  the 
formation  of  sugar  or  from  the  amino  sugars,  and  prior  to  oxidation 
in  the  case  as  such  amino-acids  as  are  destined  to  direct  oxidation. 
The  NH3  thus  set  free  combines  in  the  circulating  fluids  with  the  ever- 
present  carbon  dioxid  to  form  ammonium  carbonate.  This  is  by 
anhydration  held  to  be  converted  into  urea  through  the  intermediary 
stage  of  ammonium  carbamate. 


THE  CATABOLISM  OF  PROTEIN  399 

Ammonium  carbonate       Ammonium  carbamate      Urea  or  carbamid 


O.NH4 

O.NH4 

NH2 

<£>       - 

<£>        - 

do 

\ 

\ 

\ 

O.NH4 

NH2 

NH2 

H20  H20 

A  molecule  of  water  is  extruded  in  each  stage,  first  one  nitrogen  group 
being  attacked  and  then  the  second.  The  reaction,  though  it  is  of  course 
to  be  termed  an  anhydration,  is  in  a  way  both  a  reduction  and  an  oxida- 
tion, since  both  hydrogen  and  oxygen  are  removed,  and  a  unit  weight 
of  urea  has  a  higher  caloric  value  than  has  the  same  weight  of  ammonium 
carbonate.  In  a  general  sense  any  reaction  that  increases  the  heat 
value  per  gram  of  a  substance  may  be  termed  a  reduction. 

The  experimental  reasons  that  prove  this  scheme  of  reaction  are  many. 
Ammonium  carbonate  and  ammonium  carbamate  are  converted 
into  urea  in  the  living  body  and  in  experiments  by  perfusion  or  with 
isolated  organs.  A  fresh  liver  pulp  will  form  urea  from  ammonium 
salts  and  amino-acids.  All  ammonium  salts  that  in  the  body  are  con- 
vertible into  ammonium  carbonate  are  eliminated  as  urea.  The  blood 
of  the  portal  vein  contains  demonstrable  traces  of  ammonia,  that  of 
the  general  circulation  does  not.  This  ammonia  of  the  portal  vein 
comes  from  superfluous  amino-acids  that  have  not  been  used  in  the 
synthesis  of  the  stock  proteins  of  the  blood  in  the  wall  of  the  intestine, 
and  also  from  the  ammonia  set  free  in  the  acts  of  digestion  and  by 
bacterial  action  in  the  intestine.  This  ammonia  is  in  the  liver  converted 
into  urea.  The  urine  contains  both  ammonium  and  carbamate  salts, 
the  latter  in  mere  traces.  By  the  administration  of  large  amounts  of 
calcium  hydrate,  the  amount  of  carbamate  can  be  greatly  increased. 
And  in  the  urine  of  the  dog  following  the  establishment  of  an  Eck 
fistula,  demonstrable  amounts  of  carbamate  may  be  found  in  the  blood. 
These  facts  point  to  the  existence  of  ammonium  carbonate  and  ammo- 
nium carbamate  in  normal  blood.  From  all  the  known  facts  we  may, 
therefore,  regard  this  as  the  modus  operandi  of  the  formation  of  urea; 
the  splitting  off  the  NH2  groups  of  amino-acids  to  form  NH3,  the  com- 
bination of  NH3  with  C02  to  form  ammonium  carbonate,  and  the 
anhydration  of  this  salt  to  urea  through  the  intermediary  stage  of 
ammonium  carbamate. 

Recent  chemical  investigations  have  indicated  a  way  in  which  urea 

might  be  formed  from  amino-acid  by  the  direct  combination  of  carbon 

dioxid  with  the  NH2  groups  of  amino-acids,  in  other  words,  prior  to 

deaminization.     This  is  indicated  in  the  following  reactions.     When 

C02  is  passed  into  a  solution  of  an  amino-acid  and  calcium  hydrate, 

compounds  of  the  type  of 

/H 
R  —  N< 

XJOOH 

:ooh 


i< 


400  THE  METABOLISM  OF  PROTEIN 

are   formed.      Illustrations   for  glycocoll   and   alanin   will   make   the 
application  clear. 

Calcium  carbamino-acetate  Calcium  carbamino-propionate 


CH2  —  N  —  COO  CH3 

COO Ca  H  —  C  —  NH  —  COO 

I  I 

COO Ca 

In  other  words,  by  the  direct  combination  of  carbon  dioxid  with*  amino- 
acids  carbamino  acids  are  formed,  whose  conversion  into  urea  would 
naturally  follow.  In  this  scheme,  which  lacks  experimental  confirma- 
tion in  animals,  the  intermediary  stage  would  be  the  one  previously 
given,  carbamate. 

Urea  is  also  formed  in  the  body,  in  small  but  indeterminate  amounts, 
from  creatinin  and  uric  acid.  These  derivations  will  be  discussed  in  the 
connection  with  the  catabolism  of  these  two  substances. 

The  formation  of  urea  is  so  continuous  and  the  elimination  so  prompt 
that  the  circulating  blood  is  practically  free  of  urea,  as  it  is  indeed 
practically  free  of  NH2  nitrogen.  Even  with  the  formation  of  as  large 
an  amount  as  80  grams  per  day,  which  would  be  a  stupendous  protein 
catabolism,  the  blood  of  the  entire  body  would  contain  in  any  one 
second  less  than  ten  milligrams  of  urea.  Of  course,  it  is  not  equally  dis- 
tributed in  all  the  circulating  fluids.  The  larger  part  would  be  in  the 
blood  poured  from  the  liver  into  the  venous  circulation.  Urea  is  indeed 
formed  in  other  organs  and  tissues  than  the  liver,  or  at  least  may  be. 
Furthermore,  the  formation  of  urea  occurs  in  waves.  The  formation  of 
the  endogenous  urea  may  be  regarded  as  a  continuous  and  even  pro- 
cess. But  the  catabolism  of  the  excess  of  protein  in  the  diet  with  the 
formation  of  the  exogenous  urea  occurs  during  the  few  hours  following 
the  ingestion  of  the  protein  in  question.  But  even  at  the  crest  of  the 
wave  of  urea  formation,  while  the  blood  drawn  from  the  hepatic  vein 
might  be  expected  to  contain  demonstrable  amounts  of  urea,  it  is  clear 
that  the  blood  of  the  peripheral  vessels  could  not  be  expected  to  con- 
tain urea  in  demonstrable  amounts.  The  elimination  of  urea  by  the 
kidneys  is  apparently  a  very  complete  one.  In  another  place,  evidence 
will  be  adduced  to  indicate  that  retentions  of  urea  occur  under  a  number 
of  different  physiological  and  pathological  conditions,  though  it  is 
not  certain  that  the  fault  lies  in  the  kidney.  But  under  ordinary  cir- 
cumstances, the  elimination  of  urea  appears  to  be  one  of  the  most  easy, 
ready  and  quantitative  functions  of  the  kidney. 

It  was  stated  above  that  there  is  evidence  that  other  organs  than 
the  liver  can  form  urea  from  ammonium  carbonate  and  carbamate. 
This  is  true  in  the  sense  that  splenic  pulp,  for  example,  will  form  small 
amounts  of  urea  from  amino-acids.  Urea  accumulates  in  the  blood 
of  a  dog  whose  liver  and  kidneys  have  been  shut  out  of  the  circulation, 


THE  CATABOLISM  OF  PROTEIN  401 

proving  that  the  formation  of  urea  from  ammo-acids  continues  in  the 
absence  of  the  liver.  There  can,  therefore,  be  no  question  that  as  an 
adaptative  function  other  tissues  than  the  liver  can  carry  on  the  forma- 
tion of  urea.  On  the  other  hand,  it  is  very  striking  to  what  an  extent 
the  urea-forming  function  of  the  liver  is  retained  in  profound  experi- 
mental degenerations  of  the  liver.  Whether  tissues  other  than  the 
liver  do  form  urea  in  the  living  organism,  is  another  and  unproved 
question.  The  animal  with  an  Eck  fistula  is  often  regarded  as  an 
illustration  of  the  formation  of  urea  in  tissues  other  than  the  liver. 
This  rests  upon  a  misconstruction  of  the  protein  catabolism,  according 
to  the  interpretation  here  accepted.  The  portal  blood  carries  to  the 
liver  only  the  ammo-acids  that  have  been  found  superfluous  (on  the 
particular  days),  in  the  building  of  serum  albumin  and  serum  globulin 
in  the  intestinal  wall.  If  an  animal  were  to  be  fed  on  the  serum  albumin 
and  serum  globulin  of  another  animal  of  its  own  species,  even  these 
would  not  be  present  to  be  carried  to  the  liver.  This  small  fraction 
alone  is  all  the  amino-acid  that  the  portal  blood  contributes  to  the 
liver.  The  larger  mass  of  amino-acids  that  makes  up  the  urea  forma- 
tion comes  from  the  catabolism  of  protein  within  the  various  body 
cells  (including  here  the  superfluous  amino-acids  that  are  set  free  in 
the  syntheses  of  the  special  proteins  from  the  stock  blood  proteins) 
and  from  the  catabolism  of  the  excess  of  protein  in  the  diet,  the  excess 
of  the  two  stock  proteins  formed  therefrom.  Now  the  amino-acids  of 
the  endogenous  catabolism  of  protein  in  the  various  cells  of  the  body 
are  carried  to  the  liver  in  the  arterial  circulation.  And  the  excess  of 
the  stock  proteins  of  the  blood,  the  result  of  an  excessive  ingestion  of 
protein,  are  of  course  carried  to  the  liver  in  the  arterial  blood;  merely 
switching  the  portal  vein  to  the  inferior  vena  cava  does  not  keep  them 
out  of  the  liver,  it  simply  results  in  sending  them  to  the  liver  via  the 
general  circulation  instead  of  through  the  portal  circulation.  It  is 
furthermore  a  priori  most  likely  that  at  all  times  the  catabolism  of 
excessive  protein  in  the  liver  follows  its  deposition  there  from  the 
arterial  circulation  instead  of  from  the  portal  circulation.  Be  this 
as  it  may,  it  is  clear  that  the  establishment  of  an  Eck  fistula  merely 
sends  the  excessive  stock  proteins  to  the  liver  via  the  arterial  circulation 
instead  of  via  the  portal  circulation.  The  liver  contains  supposedly 
one-sixth  of  the  blood  of  the  body.  And  though  the  portal  blood  makes 
up  a  goodly  fraction  of  this,  the  circulation  through  the  hepatic  artery 
is  a  very  free  and  adaptable  one.  Now  because  under  these  circum- 
stances urea  is  formed  as  under  normal  conditions,  it  is  not  at  all  to 
be  assumed  that  this  urea  is  formed  outside  of  the  liver.  Surely  no 
one  would  advance  the  proposition  that  the  liver  can  only  form  urea 
from  protein  when  it  is  presented  to  it  by  the  portal  circulation.  So 
far  as  the  data  relating  to  all  the  different  functions  of  the  liver  are 
concerned,  including  herein  the  known  facts  for  carbohydrates,  fats, 
proteins  and  pharmacological  substances,  it  is  clear  that  the  liver 
has  the  same  chemical  powers  to  apply  to  substances  that  reach  it 
26 


402  THE  METABOLISM  OF  PROTEIN 

via  the  arterial  circulation  as  via  the  portal  circulation.  We  may, 
therefore,  regard  the  formation  of  urea  in  animals  with  an  Eck  fistula 
as  occurring  in  the  liver;  and  although  the  formation  of  urea  in  other 
organs  and  tissues  may  be  conceded,  to  what  extent  it  occurs  is  unknown. 
If  the  liver  be  not  under  all  physiological  circumstances  the  sole  organ 
for  the  formation  of  urea,  it  is  at  least  the  chief  organ. 

When  the  total  relations  of  the  formation  of  urea  are  contemplated, 
it  is  clear  that  there  are  two  fractions  in  the  urea  output  whose  mean- 
ing is  different  and  which  we  ought  to  keep  separated,  namely,  the 
endogenous  and  the  exogenous  urea.  This  distinction  is  of  great  impor- 
tance to  the  theory  of  metabolism;  and  the  question  of  the  protein 
needs  of  the  body  is  only  another  phase  or  aspect  of  this  general  matter. 
We  shall  later  observe  similar  distinctions  in  creatinin  and  the  purins. 
For  urea  the  necessity  or  the  advantage  of  this  distinction  has  only 
recently  become  fully  apparent.  At  the  same  time,  it  is  clear  that 
the  quantitative  experimental  separation  of  the  endogenous  from  the 
exogenous  urea  has  not  yet  been  definitely  accomplished.  And  while 
we  know  enough  to  realize  that  the  relations  are  to  some  extent  adapt- 
able and  not  rigid,  we  must  expect  in  the  future  to  secure  a  more  clear- 
cut  line  of  demarcation  than  we  possess  today.  The  urea  of  endogenous 
protein  catabolism,  the  catabolism  of  protoplasmic  protein,  probably 
does  not  exceed  5  to  7  grams  per  day  for  a  body  of  70  kilos  when  the 
subject  is  on  a  carbohydrate  diet  covering  the  needs  of  the  body  with 
just  enough  protein  to  establish  an  equilibrium  in  nitrogen.  It  is  not 
related  to  the  creatin  of  the  muscular  metabolism.  It  is  derived  largely 
from  the  catabolism  of  protoplasm  of  the  cells  of  the  glandular  organs, 
though  probably  all  cells  have  a  slight  urea  production.  The  vastly 
larger  mass  of  urea  eliminated  under  ordinary  conditions  is  derived 
from  the  catabolism  of  exogenous  protein,  the  excess  of  protein  in  the 
diet. 

Endogenous  Urea. — The  urea  derived  from  endogenous  sources 
comprises  several  fractions,  (a)  The  urea  derived  from  the  autolysis 
of  dead  cells.  It  is  our  conviction  that  the  protein  of  the  protoplasm 
of  such  cells  is  completely  catabolized  and  eliminated,  (b)  The  urea 
derived  from  protein  catabolized  in  the  wear  and  tear  of  living  func- 
tionating cells,  (c)  The  urea  derived  from  the  catabolism  of  the  amino- 
acids  that  are  found  superfluous  when  the  cells  of  the  body  form  special 
proteins  from  the  stock  proteins  of  the  blood  plasma,  (d)  The  urea 
derived  from  the  catabolism  of  the  amino-acids  found  superfluous  when 
the  body  forms  the  stock  proteins  of  the  blood  plasma  from  the  products 
of  the  digestion  of  the  proteins  of  the  diet.  This  fraction  may  be  quite 
large;  if  a  dog  were  fed  on  canine  blood  serum,  it  would  be  nil.  (e) 
The  urea  derived  in  the  conversion  of  endogenous  creatinin  into  urea. 
(/)  The  urea  derived  in  the  conversion  of  endogenous  purins  into  urea. 
Fractions  (e)  and  (/)  have  not  been  found  measurable,  but  on  a  fixed 
diet  under  constant  conditions  of  life,  they  may  probably  be  regarded 
as  subject  to  but  slight  variations.    All  these  derivations  of  urea  are 


THE  CATABOLISM  OF  PROTEIN  403 

subject  to  slight  variations,  dependent  upon  the  age  of  the  individual, 
the  requirements  for  growth,  the  conditions  of  general  nutrition  prior 
to  the  experiment,  the  state  of  the  muscular  tissues,  the  amounts  of 
sugar  and  fat  in  the  diet,  and  upon  other  occasional  and  individual 
factors.  While  it  ought  to  be  possible  to  define  a  ratio  of  endogenous 
urea  to  total  protein  content  of  the  body,  it  is  not  possible  to  define 
an  accurate  ratio  of  endogenous  urea  to  body  weight,  on  account  of 
variations  in  skeleton,  connective  tissues,  and  fat — just  as  it  is  not 
possible  to  define  an  accurate  caloric  ratio  for  body  weight. 

The  ammonia  of  the  urine  may  be  regarded  as  a  portion  of  both 
the  exogenous  and  endogenous  urea.  When  the  exogenous  urea  is 
reduced  experimentally,  the  ammonia  fraction  falls  correspondingly; 
but  if  the  exogenous  urea  be  entirely  withdrawn,  urinary  ammonia  is 
still  present  and  belongs  to  the  endogenous  urea. 

The  neutral  sulphur  of  the  urine  tends  to  hold  itself  parallel  to  the 
endogenous  urea,  independent  of  the  total  nitrogen  input  and  of  the 
total  sulphur  output. 

Exogenous  Urea. — The  exogenous  urea  comprises  two  fractions. 
(a)  The  urea  formed  from  exogenous  ammonia,  amino-acids,  creatinin, 
and  purins  (these  bodies  being  contained  in  the  diet)  and  from  any 
other  substances  in  the  diet  that  may  be  in  whole  or  part  convertible 
into  urea.  This  fraction  is  usually  not  large,  and  it  can  be  excluded 
by  appropriate  diet;  a  milk  diet  for  example,  is  practically  free  of  such 
urea-forming  substances.  (6)  The  urea  formed  from  the  catabolism 
of  protein  ingested  in  excess  of  the  needs  of  the  body  for  anabolism 
and  replacement  for  wear  and  tear  of  protoplasm.  This  fraction  of 
urea  represents  superfluity  in  protein  ingestion.  The  body  maintains 
a  fixed  concentration  of  protein  in  the  circulating  fluids  surrounding 
the  cells.  There  is  no  storage  state  for  protein,  corresponding  to  glycogen 
and  fat.  To  a  limited  extent  the  cells  of  the  body  can  lay  on  a  little 
protoplasm,  just  as  they  can  tolerate  a  certain  attenuation.  But  this 
state  of  protein  storage  is  very  limited.  Whenever  the  ingestion  of 
protein  adds  to  the  circulating  fluids  protein  above  the  needs  of  the 
body,  the  body  maintains  constant  the  protein  concentration  of  its 
circulating  fluids  by  the  prompt  catabolism  of  the  excessive  protein. 
The  result  of  this  operation  is  exogenous  urea.  If,  on  the  other  hand, 
less  protein  be  ingested  that  corresponds  to  the  needs  of  the  tissues, 
to  preserve  constant  the  concentration  of  protein  in  the  circulating 
fluids,  the  body  transforms  protein  of  tissues  of  low  grade  into  blood 
proteins.  Adaptations  there  are.  In  youth  the  processes  of  anabolism 
may  display  a  sort  of  wasteful  excess;  under  conditions  of  subnutrition 
and  in  old  age  the  processes  of  anabolism  are  very  effective  and  eco- 
nomical. These  variations  are,  of  course,  indirectly  reflected  in  the 
figure  for  exogenous  urea,  since  the  exogenous  urea  is  all  urea  above 
that  present  in  the  urine  when  the  body  is  in  exact  minimum  nitrogenous 
equilibrium  under  the  conditions  of  the  particular  experiment.  The 
elimination  of  oxidized  sulphur  in  the  urine  tends  to  run  parallel  ,to 


404  THE  METABOLISM  OF  PROTEIN 

the  exogenous  urea,  being  very  low  on  a  minimal  protein  input  and 
rising  as  the  input  of  protein  is  increased.  The  curve  of  the  oxidized 
sulphur  elimination  resembles  that  of  the  elimination  of  nitrogen, 
but  it  is  completed  in  less  time.  While  the  cystein  of  protein  is  not 
all  split  early  in  the  course  of  digestion,  some  of  it  being  contained 
in  the  final  fractions  of  peptone,  nevertheless  the  exogenous  oxidized 
sulphur  is  very  quickly  eliminated. 

The  elimination  of  the  exogenous  urea  follows  a  fairly  definite  course. 
The  curve  of  elimination  rises,  beginning  at  about  three  hours  after  the 
ingestion  of  the  protein,  reaching  its  height  by  the  sixth  or  seventh 
hour  (by  which  time  half  of  the  nitrogen  will  usually  have  been  re- 
covered) and  then  falls  away,  reaching  the  base  line  at  from  twelve  to 
twenty  hours.  If  the  ration  of  protein  be  excessive  and  especially  if 
repeated  regularly,  the  completion  of  the  elimination  of  the  exogenous 
urea  may  be  delayed  for  several  days.  Different  proteins  are  catab- 
olized  with  sometimes  strikingly  different  velocities.  Thus  the  nitrogen 
of  casein  is  quickly  recovered;  that  of  egg  albumin  is  not  entirely 
recovered  for  several  days. 

Taking  into  consideration  all  the  varying  factors,  it  is  possible  to 
give  an  approximate  estimate  of  the  endogenous  urea.  In  an  adult 
individual  (over  twenty-five  years)  in  good  natural  nutrition,  living 
under  normal  conditions  of  work,  the  experiment  not  having  been 
preceded  by  a  season  of  hard  physical  work  or  of  physical  illness,  the 
body  fat  not  being  excessive  and  the  diet  containing  enough  sugar 
and  fat  to  cover  independently  of  the  protein  the  maximum  heat  needs 
of  the  body  under  the  conditions  of  the  experiment,  the  endogenous 
urea,  including  the  ammonia,  may  be  said  to  vary  from  100  to  170 
milligrams  urea  per  kilo  per  day,  these  differences  expressing  individual 
variations,  women  inclining  to  the  lower  figure,  men  inclining  to  the 
upper  figure.  Exceptional  individuals  may  present  still  lower  figures; 
occasional  individuals,  in  apparent  health,  may  seem  to  require  more. 
All  urea  in  excess  of  these  figures  is  exogenous  urea.  Thus  the  urea 
nitrogen  is  commonly  85  to  90  per  cent,  of  the  total  nitrogen;  with 
the  exogenous  urea  restricted  by  a  low  but  adequate  protein  diet,  the 
urea  nitrogen  will  not  be  over  60  to  65  per  cent,  of  the  total  nitrogen; 
the  amount  will  be  6  to  10  grams,  instead  of  15  to  30  grams.  Where 
climatic,  industrial,  religious  or  economic  factors  operate  to  lower  the 
consumption  of  meat,  this  result  of  dietetic  luxury  is  less  in  evidence. 
In  few  peoples  of  the  earth,  however,  does  total  urea  approximate 
endogenous  urea. 

Elimination  of  Urea. — Urea  is  eliminated  largely  but  not  exclusively 
by  the  kidneys.  There  is  urea  in  the  secretions  of  the  skin  and  in  the 
stools,  in  each  instance  excrementitious.  The  variations  in  these  elimi- 
nations may  be  considerable.  Profuse  perspiration  and  diarrhea 
increase  largely  the  urea  (nitrogen)  output  of  skin  and  intestine. 
Normally  probably  not  over  a  half  gram  of  urea  is  thus  eliminated 
per  day.     But  with  profuse  perspiration,  nitrogen  corresponding  to 


THE  CATABOLISM  OF  PROTEIN  405 

over  2  grams  of  urea  may  be  eliminated  by  the  skin,  and  equal  figures 
may  be  noted  in  active  diarrhea.  Whether  under  conditions  of  reten- 
tion of  urea,  as  is  sometimes  seen  in  cardiac  dropsy  and  in  nephritis, 
the  urea  eliminating  functions  of  the  skin  and  intestine  are  especially 
active,  as  has  been  long  assumed  by  clinicians,  is  not  known.  If  the 
concentration  of  urea  in  the  circulating  fluids  be  increased,  increased 
elimination  by  the  skin  and  intestine  would  be  naturally  expected; 
and  if  the  kidneys  by  reason  of  disease  were  less  permeable  to  urea, 
this  might  show  in  the  nitrogen  output  of  the  skin  and  feces.  But 
no  such  thing  has  ever  been  demonstrated,  and  the  results  of  purga- 
tion and  of  drug  diaphoresis  have  not  been  such  as  to  make  a  so-called 
vicarious  elimination  of  urea  by  skin  and  intestine  appear  certain. 
And  in  any  event,  the  amounts  involved  cannot  be  very  large.  Most 
of  the  work  dealing  with  the  elimination  of  urea  by  skin  or  intestine 
has  been  done  in  the  absence  of  controls,  and  with  no  idea  of  the  amount 
of  urea  to  be  expected  from  the  input  of  protein;  inevitably,  therefore, 
the  inferences  are  not  founded  upon  figures  that  are  to  be  considered 
trustworthy. 

There  is  no  elimination  of  urea,  or  any  form  of  catabolized  nitrogen, 
in  the  expired  air. 

Ammonia. — There  is  a  small  fraction  of  ammonia  split  off  in  the 
digestive  hydrolysis  of  protein.  Bacteria  evolve  ammonia  from 
amino-acids  in  the  intestine.  This  is  absorbed,  and  joins  the  ammonia 
formed  through  the  deaminization  of  amino-acids  wherever  found. 
The  urine  contains  from  200  to  600  milligrams  of  ammonia  per  day, 
depending  in  part  upon  the  amount  of  protein  in  the  diet.  The  blood 
and  tissues  contain  demonstrable  traces.  The  urine  of  children  con- 
tains more  ammonia  than  does  the  urine  of  adults.  The  elimination 
of  ammonia  in  the  urine  may  be  regarded  as  an  expression  of  equilibrium. 
When  exogenous  and  endogenous  acids  and  all  conditions  tending  to 
make  the  urine  alkaline  are  excluded,  it  is  found  that  the  ammonia  of 
the  urine  bears  a  general  relation  of  direct  proportionality  to  the  urea; 
if  the  protein  be  increased  the  ammonia  output  rises,  if  the  protein 
is  reduced  the  ammonia  output  is  lowered.  This  we  may  interpret 
to  indicate  that  in  the  blood  there  is  a  station  of  equilibrium  in  the 
reaction  whereby  urea  is  formed  from  ammonium  carbonate.  Both 
being  present  in  the  blood,  the  kidneys  eliminate  both.  That  such  a 
relation  of  equilibrium  exists  is  indicated  also  by  the  very  large  amount 
of  sodium  bicarbonate  necessary  to  reduce  the  ammonia  of  the  urine 
to  the  minimum.  If  to  a  healthy  person  some  90  grams  of  sodium 
bicarbonate  be  given  daily,  performed  ammonia  will  be  practically 
driven  from  the  urine. 

This  equilibrium  is  subject  to  disturbance,  on  the  one  hand  by  the 
ingestion  of  alkali,  and  on  the  other  hand  by  the  ingestion  or  formation 
within  the  body  of  acid.  The  amounts  of  alkali  contained  in  normal 
diets  are  not  enough  to  diminish  materially  the  amount  of  ammonia 
in  the  urine.    The  amount  of  acid  that  may  be  present  in  normal  diets 


40G  THE  METABOLISM  OF  PROTEIN 

is  also  not  enough  to  increase  materially  the  elimination  of  ammonia. 
When  mineral  acids  are  administered,  a  point  will  be  reached  when 
the  ammonia  of  the  urine  rises.  With  some  individuals,  or  at  least 
with  individuals  on  certain  diets,  a  half  gram  of  a  mineral  acid  will 
cause  no  rise  in  the  urinary  ammonia;  in  others  this  amount  will  cause 
a  rise.  With  increasing  doses,  the  amount  of  ammonia  tends  to  increase 
in  general  proportion  to  the  amount  of  acid.  The  obvious  explanation 
is  that  the  mineral  acid  combines  with  the  ammonia  circulating  as 
carbonate  or  carbamate  and  thus  withdraws  it  from  the  urea  formation. 
Turned  about,  we  say  that  the  ammonia  distoxicates  the  acid  and 
spares  the  fixed  cations  of  the  tissues.  As  a  matter  of  fact,  the  acid  is 
eliminated  combined  both  with  fixed  cations  from  the  tissues  (sodium, 
potassium,  and  calcium)  and  ammonia.  At  first  the  acid  combines 
with  all,  there  being  some  loosely  bound  sodium,  potassium,  and  calcium 
in  the  tissues.  As  the  amount  of  acid  is  increased,  more  ammonia 
relatively  and  absolutely  is  eliminated  with  the  acid.  When  the  amount 
of  acid  introduced  approaches  in  combining  value  the  total  available 
ammonia,  the  fixed  cations  of  the  tissues  are  again  drawn  upon.  In 
general,  it  has  been  thought  that  an  acidosis  was  not  of  dangerous 
import  so  long  as  the  amount  was  so  low  as  not  to  draw  upon  the 
firmly  combined  cations  in  the  tissues.  This  is  not,  however,  strictly 
true,  for  there  is  and  under  all  circumstances  must  be  some  abstrac- 
tion of  sodium,  potassium,  and  calcium  from  the  tissues;  the  law  of 
mass  action  demands  that,  it  is  impossible  to  conceive  of  acid  in  the 
body  combining  with  ammonia  alone.  Therefore,  long-continued 
acidosis  must  lead  to  dangerous  abstraction  of  cations  from  the  tissues, 
even  though  the  ammonia  elimination  be  high.  Other  things  being 
equal,  it  is  immaterial  how  the  acid  is  introduced.  Carnivora  bear 
acid  administration  by  the  mouth  better  than  herbivora,  on  account 
of  the  greater  content  of  protein  in  the  diet.  If  the  diet  of  the  carnivora 
be  reduced  in  protein  and  the  diet  of  the  herbivora  increased  in  protein, 
the  difference  in  resistance  to  acidosis  disappears.  What  has  been  said 
applies  to  organic  acids  as  well  as  to  mineral  acids.  Only  organic 
acids  that  are  incombustible  in  the  body  combine  with  ammonia  to 
be  eliminated  in  combination;  otherwise  the  acid  is  burned,  and  the 
ammonia  appears  as  urea. 

From  these  facts  it  becomes  apparent  that  increase  of  ammonia 
in  the  urine  above  the  amount  usually  seen  on  a  particular  regimen  of 
protein  is  to  be  referred  to  the  existence  of  an  acidosis.  And  in  general 
we  may  measure  the  degree  of  an  acidosis  by  estimation  of  the  urinary 
ammonia.  This  is  not  strictly  true,  since  as  stated  fixed  cations  are 
always  withdrawn  in  some  amount.  But  since  the  withdrawal  of  the 
fixed  cations  may  in  general  be  regarded  as  proportional  to  the  acidosis, 
the  estimation  of  urinary  ammonia  may  still  be  used  as  a  measurement 
of  acidosis.  And  this  gives  to  the  estimation  of  urinary  ammonia  an 
especial  importance  in  diabetes,  in  which  prolonged  acidosis  is  usually 
present,  giving  opportunity  for  a  dangerous  abstraction  of  cations 
from  the  important  tissues  of  the  body. 


THE  CATABOLISM  OF  SPECIAL  AMINO-ACIDS  407 

We  do  not  at  present  believe  in  the  existence  of  a  primary  increase 
in  the  ammonia  of  the  urine,  independent  of  acidosis,  an  increase  in 
ammonia  due  to  primary  failure  of  the  formation  of  urea  from  ammo- 
nium carbonate.  We  regard  the  urea-forming  function  as  always 
fully  competent  to  convert  all  the  available  ammonium  carbonate 
into  urea.  Beyond  the  normal  amount,  ammonia  is  eliminated  only 
when  withdrawn  from  urea  formation  by  combination  with  non-com- 
bustible acid.  Experiments  temporarily  excluding  the  liver  from  the 
circulation  and  resulting  in  pronounced  atrophy  of  the  organ  have  not 
been  found  to  have  been  uniformly  followed  by  high  ammonia  and 
low  urea;  and  in  any  event  acidosis  has  not  been  excluded.  This  point 
of  view  is  obviously  based  upon  the  idea  that  urea  is  formed  in  the 
liver  alone;  whereas  as  a  matter  of  experiment,  urea  is  formed  in  appar- 
ently normal  amounts  in  the  body  of  a  dog  whose  liver  and  kidneys 
have  been  shut  out  of  the  circulation.  Studies  in  the  urine  in  natural 
diseases  of  the  liver  indicate  that  in  some  cases  of  profound  disease 
of  the  liver,  and  also  in  eclampsia,  the  ammonia  may  be  high  and  the 
urea  low.  But  here,  too,  acidosis  has  not  been  excluded.  The  writer 
has  personally  never  seen  a  case  of  high  ammonia  content  in  urine 
without  being  able  to  demonstrate  acid  with  which  it  was  combined. 
Future  investigations  may  overthrow  this  dictum,  but  at  present  all 
the  data  point  in  the  one  direction.  The  acids  usually  concerned  are 
beta-oxy-butyric  and  aceto-acetic  acid;  but  in  some  degenerations  of 
the  liver,  lactic  acid  may  appear  in  the  urine  combined  with  ammonia. 
In  some  conditions  the  nature  of  the  acid  has  failed  of  elucidation. 

Of  the  ammonia  occurring  naturally  in  the  urine,  what  amount  is 
brought  out  by  acids,  and  what  amount  represent  the  direct  elimina- 
tion by  the  kidneys?  When  alkali  is  given  in  amounts  sufficient  to 
make  the  urine  alkaline,  ammonia  is  still  present;  as  stated  it  requires 
high  doses  of  alkali  to  render  the  urine  ammonia-free.  Theoretically, 
the  ammonia  present  in  the  urine  when  the  reaction  of  the  urine  is 
kept  faintly  alkaline  by  the  administration  of  just  sufficient  alkali, 
would  represent  the  direct  elimination;  the  amounts  over  this  and  up 
to  the  figures  observed  in  natural  urines  represent  the  fraction  related 
to  normal  acidosis.  The  relations  would  naturally  vary  with  the  total 
nitrogen.  In  an  approximate  way,  we  may  perhaps  say  that  the  direct 
elimination  of  ammonia  may  amount  to  from  0.1  to  0.2  gram  per 
day.  In  other  words,  probably  over  half  of  the  ammonia  of  normal 
urine  has  been  withdrawn  from  the  urea  output  by  the  normal  presence 
of  non-combustible  acids  of  metabolic  or  dietetic  origin. 

THE   CATABOLISM   OF   SPECIAL    AMINO-ACIDS 

The  stated  scheme  of  the  catabolism  of  the  different  amino-acids, 
while  of  general  application,  is  with  a  number  of  the  amino-acids  sub- 
ject to  qualitative  and  quantitative  deviations  that  are  of  importance. 
These  we  will  consider  here. 


408  THE  METABOLISM  OF  PROTEIN 

Glycocoll. — A  hundred  grams  of  mixed  proteins,  such  as  are  to  be 
found  in  an  ordinary  diet,  will  contain  from  2  to  5  grams  of  glycocoll. 
Normally  glycocoll  is  found  in  the  bile  in  combination  as  glycocholate. 
It  is  frequently  found  free  in  normal  urine,  and  is  possibly  a  constant 
constituent  of  urine.  It  occurs  in  normal  urine  in  combination  with 
benzoic  acid  as  hippuric  acid.  It  can  be  recovered  in  the  decomposi- 
tion of  the  purins,  and  conversely  the  purins  may  be  synthesized  from 
glycocoll;  but  we  do  not  regard  either  of  these  reactions  as  occurring 
in  the  body.  It  exists  preformed  in  the  muscle  tissue  of  many  inverte- 
brates, but  it  is  not  present  in  the  muscle  of  the  higher  animals  except 
as  a  component  amino-acid.  Ox  blood  contains  free  glococoll;  the 
blood  of  carnivora  has  not  been  tested. 

The  bound  fractions  in  the  urine  are  two:  one  an  undefined  com- 
bination that  is  easily  split  off  by  weak  alkali;  secondly,  hippuric  acid. 
By  the  administration  of  benzoic  acid  it  is  possible  to  show  that  much 
more  glycocoll  is  eliminated  thus  combined  than  can  be  accounted  for 
in  the  normal  protein  catabolism.  It  is  clear  that  under  such  circum- 
stances as  the  presence  of  large  amounts  of  benzoic  acid,  glycocoll 
is  synthesized.  This  amino-acid,  it  will  be  recalled,  is  in  the  body 
convertible  into  glucose.  And  conversely,  its  derivation  from  glucose 
might  be  anticipated.  This  appears  all  the  more  likely  when  it  is  re- 
called that  the  organism  is  known  to  be  able  to  convert  a-ketonic  acids 
into  the  corresponding  a-amino-acids,  thus: 

R  R 

CO  -*  CHNH2 

COOH  COOH 

But  the  facts  of  elimination  in  animals  receiving  benzoic  acid  speak 
against  this  inference.  If  glycocoll  were  synthesized  from  sugar  and 
ammonia,  the  total  nitrogen  of  the  urine  would  not  be  altered.  As  a 
matter  of  fact  it  is  increased,  and  increased  much  more  than  the  amount 
of  nitrogen  in  the  hippuric  acid  concerned.  When  the  nitrogen  frac- 
tions of  the  urine  during  the  course  of  the  experiment  are  determined, 
it  is  found  that  the  increase  in  nitrogen  output  over  and  above  the 
hippuric  acid  lies  in  the  rest-fraction,  it  is  not  urea.  From  this  two 
inferences  seem  justified:  the  glycocoll  is  derived  from  the  disintegra- 
tion of  protein  somewhere  in  the  body;  and  this  disintegration  differs 
from  the  normal  catabolism  of  protein,  in  that  the  major  product  is 
not  urea,  but  more  complex  derivatives  of  amino-acids,  if  not  amino- 
acids  themselves.  Benzoylated  amino-acids  (alanin,  phenylalanin, 
leucin,  valin,  serin,  aspartic  acid,  glutamic  acid  and  ornithin)  when 
administered  parenterally  are  eliminated  unchanged — not  converted 
into  hippuric  acid.  The  body  proteins  that  contain  large  amounts  of 
glycocoll  belong  to  the  connective-tissue  group,  which  one  would  most 
naturally  expect  to  see  built  down.  Beyond  this  there  is  but  one  alterna- 
tive: glycocoll  must  be  derived  from  amino-acids  higher  in  the  fatty 
acid  scale,  possibly  in  the  kidney.     How  this  could  be  done  we  do 


THE  CATABOLISM  OF  SPECIAL  AMINO-ACIDS  409 

not  know.  Reactions  of  oxidation  and  cleavage,  attacking  the  beta 
carbon,  have  been  suggested.    This  may  be  illustrated  for  alanin: 

CH3  C02  H20 

CHNH2         ->  CH2NH2 

COOH  COOH 

Such  a  reaction  is  purely  hypothetical.  The  animal  forms  glycocoll 
from  other  amino-acids,  of  that  there  is  little  doubt,  but  we  do  not 
know  how. 

The  Aromatic  Amino-acids. — These  include  phenylalanin,  tyrosin, 
and  tryptophan.  It  is  the  current  teaching  that  these  aromatic  bodies 
when  set  free  in  the  protein  catabolism  of  the  tissues  are  completely 
burned.  All  the  aromatic  acids  and  other  combinations  in  the  urine 
are  held  to  have  been  resorbed  from  the  intestinal  tract.  It  is  known 
that  under  certain  circumstances  the  body  ruptures  the  benzene  ring 
and  burns  it,  and  this  is  what  occurs  in  the  cellular  metabolism.  In 
the  intestinal  tract,  on  the  other  hand,  bacteria  carry  on  different 
processes  with  the  same  amino-acids,  the  products  of  which  on  resorp- 
tion into  the  body  are  not  combustible,  and  are  eliminated  largely  in 
conjugated  form.  This  is  held  to  apply  to  all  the  phenyls,  indols, 
and  even  benzoic  acid:  all  are  held  to  have  been  derived  from  the 
intestinal  tract,  none  from  the  tissue  catabolism  of  protein.  It  is  true 
that  many  substances  that  are  commonly  supposed  to  act  as  intestinal 
antiseptics  reduce  the  aromatic  bodies  in  the  urine  to  a  trace.  It  is 
true  that  the  restriction  of  the  diet  to  milk  and  meat  reduces  to  a 
minimum  the  hippuric  acid  of  the  urine,  since  many  fruits  and  vegetables 
contain  benzoic  acid  in  one  or  another  state,  and  bacterial  fermenta- 
tion of  vegetables  sets  free  or  forms  still  another  fraction.  It  is  certain 
that  the  stools  always  contain  aromatic  bodies  derived  by  bacteria 
from  the  aromatic-containing  amino-acids  of  the  products  of  digestion. 
And,  finally,  aromatic  amino-acids  introduced  into  the  organism  are 
promptly  burned,  and  do  not  reappear  in  the  urine.  It  is,  therefore, 
highly  probable  that  the  phenyl,  indol,  and  benzoate-containing  bodies 
in  the  urine  are  derived  from  the  alimentary  tract,  and  that  the  benzene 
of  the  amino-acids  of  protein  of  tissue  catabolism  is  burned.  The  evi- 
dence for  this  view  is  strong,  but  cannot  be  regarded  as  conclusive. 
The  conclusive  demonstration  would  be  furnished  by  benzene-free 
urine  obtained  from  animals  so  reared  as  to  have  preserved  the  ali- 
mentary tract  free  of  bacteria.  In  one  instance,  in  guinea-pigs,  in 
which  animals  have  been  reared  with  sterile  alimentary  tracts,  traces 
of  p-oxy-phenyl-acetic  and  p-oxy-phenyl-propionic  acids  were  found 
in  the  urine,  but  no  indol,  phenol,  kresol,  or  hippuric  acid. 

The  steps  in  the  rupture  of  the  benzene  ring  and  the  reactions  of 
combustion  are  not  well  known.  The  few  facts  we  possess  have  been 
derived  from  the  study  of  alcaptonuria.  The  substance  termed  alcapton 
(homogentisic  acid)  is  dioxy-phenyl-acetic  acid  (hydroquinone  acetic 
acid).     When  this  substance  is  introduced  into  the  body  of  a  normal 


410 


THE  METABOLISM  OF  PROTEIN 


individual,  it  is  burned.  When  introduced  into  the  body  of  an  alcapto- 
nuric,  it  reappears  in  the  urine  in  toto.  The  condition  of  alcaptonuria, 
which  is  a  harmless  pathological  deflection  often  running  in  families,  has 
been  usually  interpreted  to  be  an  instance  of  the  checking  of  a  series  of 
reactions  at  the  stage  of  an  intermediary  substance.  It  is  assumed  that 
in  the  normal  individual  the  tyrosin  and  phenylalanin  are  burned 
through  dioxyphenyl-acetic  acid  to  the  end  products,  with  rupture  of 
the  benzene  ring.  In  the  individual  with  alcaptonuria,  the  reaction 
does  not  proceed  farther  than  the  stage  of  dioxyphenyl-acetic  acid. 
This  recalls  the  condition  in  diabetes,  in  which  the  combustion  of  the 
lower  fatty  acids  is  checked  at  the  stages  of  b-oxy-butyric  and  diacetic 
acids.    The  relations  in  alcaptonuria  may  be  illustrated  in  equations. 


Tyrosin 


P-oxy-phenyl-lactic  acid      Dioxy-phenyl-lactic  acid 


Dioxy-phenyl-acetic  acid 


COH 

COH 

COH 

COH 

/\ 

/\ 

/\ 

/\ 

HC        CH 

HC        CH 

HC        CH 

HC        CH 

HC        CH 

-         1             1     -> 
HC        CH 

HC        C  —  CH2 

HC        C  —  CH2 

v 

V 

V       1 

V       1 

c 

COH 

COH       ] 

1 

1 

CHOH 

COOH 

CH2 

CH2 

1 

CHNH2 
COOH 

1 

COOH 

CHOH 
COOH 

Phenylalanin 

Phenyl-lactic  acid 

Dioxy-phenyl-lactic  acid 

Dioxyphenyl-acetic  acid 

CH 

CH 

COH 

COH 

/\ 

/\ 

/\ 

/\ 

HC        CH 

HC        CH 

HC        CH 

HC        CH 

HC        CH 

HC        CH 

1 

I 

HC        C— CH2 

HC        C— CH2 

v 

c 

V 

V     1 

COH    | 

V     1 

COH    1 

CH2 

1 

CHOH 

COOH 

CH2 

1 

1 

1 

COOH 

CHNH2 
COOH 

CHOH 

COOH 

■ 

In  the  normal  catabolism  of  dioxyphenyl-acetic  acid,  the  ring  is  rup- 
tured and  both  ring  and  aceto-acetic  acid  burned;  in  the  alcaptonuric, 
this  rupture  of  the  ring  cannot  be  accomplished  and  the  compound 
is  eliminated  unchanged.  There  are  but  two  points  in  the  scheme 
that  demands  discussion.  It  is  clear  that  in  the  intestine  the  tyrosin 
is  converted  first  into  p-oxy-phenyl-propionic  acid  and  this  into 
p-oxy-phenyl-acetic  acid.  Phenylalanin  is  built  down  in  the  same 
way  in  the  intestine,  and  yields  phenyl-acetic  acid.  Now  phenyl- 
acetic  acid  will  not  yield  dioxyphenyl-acetic  acid  in  the  alcaptonuric, 
so  the  processes  must  be  different  within  the  body.  There  is  experi- 
mental evidence  that  phenylalanin  is  converted  into  the  corresponding 


THE  CATABOLISM  OF  SPECIAL  AM  I  NO-AC  IDS 


411 


lactic  acid,  instead  of  into  propionic  acid;  and  the  same  may  be  held 
to  occur  with  tyrosin.  This  has  been  indicated  in  the  equations.  The 
second  point  concerns  the  transfer  of  the  acid  group  from  the  para 
position,  since  in  the  dioxyphenyl-acetic  acid  the  two  OH  groups 
occupy  the  para  position.  This  seems  to  be  the  rule  in  certain  oxida- 
tions of  the  benzene  ring.  For  example,  when  paracresol  is  oxidized  by 
potassium  persulphate  in  acid  solution,  homo-hydroquinon  is  formed: 


COH 

HC   CH 

I    I 
HC   CH 

C.CH3 


COH 
HC   CH 
HC   C.CH3 

COH 


The  alkyl  group  is  here  seen  to  have  been  shifted,  just  as  in  the  case 
of  the  oxidations  of  the  phenyl-lactic  and  the  p-oxy-phenyl-lactic  acid 
to  dioxy-phenyl-lactic  acid.  It  is  of  course  possible  that  the  p-oxy-phenyl- 
lactic  acid  is  first  converted  into  p-oxy-phenyl-acetic  acid  and  this  then 
converted  into  dioxy-phenyl-acetic  acid;  and  the  same  thing  would  hold 
true  for  phenylalanin.  But  this  is  made  improbable  by  the  experi- 
mental fact  that  in  the  alcaptonuric,  phenyl-acetic  acid  does  not  yield 
homogentisic  acid. 

Another  formulation  is,  however,  possible,  and  one  that  has  both 
theoretical  and  experimental  evidence  in  its  favor.  Tyrosin  and  phenyl- 
alanin, instead  of  passing  into  the  stage  of  lactic  acid,  are  assumed  to 
pass  into  the  state  of  pyruvic  acid,  then  through  an  intermediary 
quinonoid  stage  into  dioxyphenyl-acetic  acid. 


Tyrosin 

COH 


P-hydroxy-phenyl-pyruvic  acid 


Quinonoin  stage 


HC 

I 
HC 


CH 

I 
CH 


y 

CH2 

CHNH2 

COOH 


HC 

I 
HC 


COH 


CH 

I 
CH 


CO 


HC 

I 
HC 


V 


CH 

ch 


2-5-dihydroxy-phenyl-pyruvic  acid 

COH 


CH2 

Ao 

I 
COOH 

Dioxy-phenyl  acetic  acid 

COH 


HO  CH2 


Ao 


HC 
Hi 


CH 

— CH2 

I 
COH  CO 

I 
COOH 


HC' 
HC 


CH 

I 

C — CH2 


COH  COOH 


I 
COOH 

Aceto-acetic  acid 

CH3 

I 
CO 

I 

CH, 

I 
COOH 


412  THE  METABOLISM  OF  PROTEIN 

Both  these  formulations  have  it  in  common  that  the  stage  of  dioxy- 
phenyl-acetic  acid  is  normal,  and  that  in  the  normal  organism  this 
homogentisic  acid  is  converted  into  aceto-acetic  acid  and  then  oxidized, 
the  remains  of  the  split  ring  also  burned.  Under  this  point  of  view  the 
defect  of  the  subject  with  alcaptonuria  lies  in  inability  to  complete 
the  series  of  reactions;  and  the  intermediate  stage,  dioxy-phenyl-acetic 
acid,  is  eliminated  unchanged.  At  the  same  time  it  is  obvious  that  the 
body  might  split  directly  the  molecule  of  2-5-di hydroxy-phenyl-pyruvic 
acid,  with  the  formation  of  aceto-acetic  acid;  and  from  this  point  of 
view  the  formation  of  dioxy-phenyl-acetic  acid  could  be  considered  an 
abnormal  reaction. 

Wholely  inconsistent  with  this  idea  are  recent  observations  to  the 
effect  that  other  simple  derivatives  of  tyrosin  and  phenylalanin  can 
be  burned  by  the  alcaptonuric,  provided  they  are  so  constituted  that 
they  cannot  pass  through  the  quinonoid  stage.  Paramethylphenyl- 
alanin  and  paraoxymethylphenylalanin,  and  their  corresponding  pyruvic 
acids,  do  not  form  paraquinonoid  derivatives,  but  are  burned  by  the 
normal  body  and  also  by  the  alcaptonuric  subject.  This  important 
observation  suggests  obviously  that  the  formation  of  the  quinonoid 
stage  and  of  homogentisic  acid  are  not  normal  but  abnormal  reactions, 
and  that  the  normal  reaction  follows  another  course.  As  formulated 
to  meet  the  experimental  facts,  the  benzene  ring  instead  of  passing 
into  the  quinonoid  state  is  split  directly,  two  of  the  carbons  of  the 
ring  joining  with  two  of  the  carbons  of  the  pyruvic  acid  to  form  aceto- 
acetic  acid.  This  interpretation  has  been  confirmed  by  the  successful 
formation  of  aceto-acetic  from  histidin.  The  illustration  for  tyrosin 
applies  also  to  phenylalanin. 

Tyrosin  Para-hydro-phenyl-pyruvic  acid       Aceto-acetic  acid 

COH  COH 


HC   CH  HC   CH 

I     I  I  ^1— 

HC    CH  HC/  CH 

V 


CH2 


C  CH3 

I  I 

CH2     -»     CO 


CHNH2             CO  CH2 

COOH  COOH 


A 


OOH 


C02 


From  this  point  of  view  the  abnormality  in  alcaptonuria  consists  in 
the  transfer  of  the  para-hydroxy-phenyl-pyruvic  acid  into  2-5-dihydroxy- 
phenyl-pyruvic  acid,  instead  of  direct  cleavage  of  the  benzene  ring  with 
the  formation  of  aceto-acetic  acid.  In  addition,  however,  the  alcapton- 
uric has  lost  the  normal  power  of  burning  homogentisic  acid.  From 
this  point  of  view,  in  a  word,  the  normal  organism  does  not  form  homo- 


THE  CATABOLISM  OF  SPECIAL  AMINO-ACIDS 


413 


gentisic  acid  from  tyrosin  but  has  the  power  of  burning  it,  while  the 
alcaptonuric  does  form  the  substance  but  has  not  the  power  of  burning  it. 

In  the  individual  with  alcaptonuria  it  seems  possible  that  a  portion 
of  the  dioxphenyl-acetic  acid  may  be  derived  from  partially  oxidized 
tyrosin  and  phenylalanin  absorbed  from  the  alimentary  tract.  When 
an  excess  of  protein  is  ingested,  the  elimination  of  alcapton  rises;  this 
may  be  due  both  to  tyrosin  and  phenylalanin  from  the  protein  catab- 
olism  and  from  the  alimentary  tract.  Sometimes  the  amount  of  diox- 
phenyl-acetic acid  is  more  than  could  have  been  expected  from  the 
protein  catabolism,  as  judged  from  the  nitrogen.  Investigations  into 
these  cases  have  indicated  that  the  subjects  were  consuming  proteins 
rich  in  aromatic  acids.  The  ratio  of  the  dioxyphenyl-acetic  acid  to 
the  nitrogen  of  the  urine  on  mixed  diet  is  usually  4  —  5  :  10,  but  in 
the  case  of  a  milk  diet,  for  example,  it  will  be  higher.  The  site  of  the 
reaction  of  the  combustion  of  the  aromatic  amino-acids  is  supposed 
to  be  the  liver. 

Epinephrin,  the  active  principle  of  the  adrenal  gland,  is  apparently 
derived  from  tyrosin,  a  transformation  suggested  by  the  tyrosinase 
reaction  of  the  adrenal  substance. 


Tyrosin 

COH 


Epinephrin 

COH 


IIC   CH 

I 
HC 


ch 


HC   COH 

I 
CH 


Hi 


c 

I 

CH2 

I 
CHNH2 

COOH 


C 

CHOH 


II, 


HNCH3 


Tryptophan.  —  Concerning  the  catabolism  of  tryptophan  we  know 
little.  The  urine  of  dogs  contains  normally  a  derivative  of  trypto- 
phan, kynurenic  acid.  This  substance  is  ;--oxy-j3-chinolin-carboxylic 
acid.    The  equations  of  the  two  substances  are  as  follows: 


Tryptophan 

CH 


HC'       C C .  CHoCHNHoCOOH 

I  I  II 

HC        C        CH 

.    v  V 

CH      NH 


HC' 

I 
HC 


Kynurenic  acid 

CH      C     (OH) 


C.COOH 
I 
CH 


CH     N 


The  path  of  transition  is  not  yet  known.  The  elimination  of  kynurenic 
acid  in  the  dog  runs  parallel  to  the  protein  catabolism;  but  incomplete 
proteins  that  do  not  contain  tryptophan,  like  gelatin,  do  not  provoke 
elimination.  If  tryptophan  be  administered  it  is  recovered  in  the 
urine  in  the  state  of  kynurenic  acid.    The  rabbit,  like  man,  does  not 


414  THE  METABOLISM  OF  PROTEIN 

normally  eliminate  kynurenic  acid  and  is  able  to  oxidize  small  amounts 
of  tryptophan;  but  when  large  amounts  are  ingested,  a  fraction  appears 
as  kynurenic  acid.  This  has  suggested  that  normally,  in  man  and  in 
most  animals,  the  tryptophan  derived  from  the  catabolism  of  protein 
in  the  tissues  is  burned  through  kynurenic  acid  as  the  intermediary 
stage ;  this  reaction,  however,  in  the  dog  being  halted  at  the  intermediary 
stage.  There  is  as  yet  no  proof  that  the  destruction  of  tryptophan  in 
the  human  body  is  thus  accomplished. 

Cystin. — The  combustion  of  cystin  in  the  body  is  always  incomplete. 
There  is  in  the  fraction  known  as  the  neutral  sulphur  of  the  urine 
unoxidized  sulphur  that  must  in  large  part,  if  not  entirely,  have  pro- 
ceeded from  cystin.  Normal  urine  may  contain  a  trace  of  cystin,  or 
cystein.  It  occurs  in  the  urine  following  phosphorus  poisoning.  And 
conversely,  in  cystinuria,  leucin  and  tyrosin  are  often  found  in  the 
urine.  The  catabolism  of  cystin  leads  to  three  directions  of  elimination : 
in  the  taurin  of  the  bile;  in  the  neutral  sulphur  of  the  urine  (part  of 
which  comes  from  taurin  possibly,  following  its  resorption  in  the  intes- 
tine); and  in  the  sulphates  of  the  urine.  There  is  a  small  amount  of 
neutral  sulphur  in  the  perspiration,  but  this  does  not  proceed  from 
the  cystin  derived  from  the  catabolism  of  protein.  Cystinuria  is  a 
rare  metabolic  anomaly,  in  which  the  urine,  blood  and  tissues  contain 
cystin,  often  in  large  amounts.  Leucin,  tyrosin  and  lysin  may  be 
present  in  the  urine.  Cystin  is  probably  found  in  the  stools  no  oftener 
than  in  normal  subjects.  The  cystin  is  identical  with  the  cystin 
obtained  in  the  acid  hydrolysis  of  protein.  The  condition  is  often 
congenital  and  runs  in  families.  The  cystin  comes  from  the  protein 
catabolism,  not  from  the  alimentary  tract.  As  a  rule,  the  amount  of 
cystin  (plus  the  other  neutral  sulphur)  in  the  urine  of  a  typical  case 
represents  the  full  sulphur  content  of  the  protein  of  the  diet.  Never- 
theless, if  cystin  be  given  by  the  mouth,  it  may  be  burned,  partially 
or  completely.  The  fraction  of  neutral  sulphur  in  the  urine  persists 
beside  the  cystin,  and  from  this  it  is  obvious  that  the  cystin  is  not 
formed  at  the  expense  of  other  neutral  sulphur.  In  some  cases  the 
defect  is  not  complete,  and  oxidized  sulphur  (sulphate)  is  to  be  found 
in  the  urine  with  the  cystin. 

The  defect  consists  obviously  in  a  failure  of  cleavage;  the  di-cy stein 
(cystin)  is  not  split,  and  the  cystein  is,  therefore,  not  available  for 
oxidation.  The  reason  why  cystin  administered  by  the  mouth  is 
burned  lies  probably  in  the  fact  that  it  is  split  in  the  alimentary  tract 
by  bacteria  and  deaminizated  in  the  intestinal  wall;  the  resorbed 
products  are  combustible  while  the  cystin  is  not  combustible. 

Cystin  Cystein  p-thio-lactic  acid  Propionic  acid 

H2CS  — SCH2  CH2SH  CH2SH  CH3 

NH2HC  CHNH2  ->  CHNH2  +  H20  =  CHOH  +  02    =    CH2       +     S03 

HOOC  COOH  COOH  COOH  COOH 

+ 
NH8 


THE  CATABOLISM  OF  SPECIAL  AMINO-ACIDS 


415 


In  cystinuria  the  amount  of  cystin  in  the  urine  is  quite  independent 
of  the  diet,  persists  during  fasting,  and  is  as  stated  not  exaggerated 
by  the  ingestion  of  cystin.  If  benzoyl  bromide  be  administered  to  a 
normal  individual  it  will  be  eliminated  combined  with  cystin — in  other 
words,  provoke  a  cystinuria.  This  is  to  be  explained  as  due  to  the 
fact  that  the  cystin  combined  with  benzoyl  resists  the  processes  of 
combustion.  It  is  not  known  whether  in  idiopathic  cystinuria  any 
substance  abstracts  the  cystin  from  the  sulphur  catabolism  in  a  similar 
manner. 

It  would  be  instructive  to  study  the  bile  of  a  case  of  cystinuria. 
In  this  way  we  could  test  the  hypothesis  that  the  taurin  is  derived 
solely  from  the  cystin  of  the  disintegrated  erythrocytes,  and  not  from 
the  cystin  of  the  common  protein  catabolism.  The  occasional  occur- 
rence of  diamins  in  the  urine  of  cystinuria  is  probably  not  of  direct 
relationship. 

Ornithin. — This  amino-acid,  derived  by  cleavage  of  arginin  in  the 
liver,  is  normally  burned.  In  rare  cases,  usually  in  connection  with 
cystinuria  though  not  in  all  cases  thereof,  there  appears  in  the  urine 
a  diamin  that  has  been  derived  from  ornithin,  tetramethylendiamin 
(putrescin).  With  this  diamin  is  usually  found  pentamethylendiamin 
(cadaverin)  derived  from  lysin.  It  is  not  invariable  to  find  the  two 
diamins  in  cystinuria;  nor  is  it  only  in  cases  of  cystinuria  that  diaminuria 
is  seen.  In  these  cases  the  diamins  are  formed  from  ornithin  and 
lysin  derived  from  the  protein  catabolism.  In  dysentery,  cholera  and 
other  severe  forms  of  enteritis,  these  same  diamins  may  be  found  in 
the  urine,  resorbed  from  the  intestinal  tract  where  they  were  formed 
from  lysin  and  ornithin  by  bacteria.  The  chemical  reaction  is  the 
same  in  tissues  or  carried  on  by  bacteria,  it  is  an  enzymic  reduction 
with  splitting  off  of  carbon  dioxid — a  reaction  very  similar  to  the 
formation  of  acetone  from  diacetic  acid  or  the  formation  of  taurin  from 
cysteinic  acid. 


Lysin 

CH2NH2 
CH2 
CH2 
CH2 

Pentamethylendiamin 
CH2NH2 

CH2 
CH2 

->        CH2 

CH2NH2 

Ornithin 

CH2NH2 

Tetramethylendiamin 
CH2NH2 

CH2 
CH2 
-♦        CHNH2 

CH2 

1 
CH2 

CHNH2 
COOH 

CHNH2 
COOH 

C02 

C02 

It  is  certain  that  these  are  qualitative  deflections,  it  cannot  be  assumed 
that  normally  these  amino-acids  are  burned  through  these  diamins. 
When  arginin,  ornithin  and  lysin  are  introduced  into  the  body  of  the 
cystinuric,  they  are  eliminated  in  the  form  of  the  stated  diamins.  When 
the  diamins  are  introduced  into  the  normal  body  they  are  eliminated 


416 


THE  METABOLISM  OF  PROTEIN 


unchanged.  The  reaction  is  held  to  occur  in  the  liver.  The  association 
with  cystinuria  is  very  obscure,  though  as  stated  all  cystinurics  have  not 
diaminuria.  The  reactions  of  cystin  and  of  lysin  and  ornithin  cannot 
touch  each  other  at  any  known  point.  When  diaminuria  occurs  with 
cystinuria,  leucin,  tyrosin  and  lysin  may  be  present  in  the  urine;  and 
evidently  there  is  both  qualitative  and  quantitative  desturbance  in  the 
catabolism  of  amino-acids.  Enzymic  reduction  with  splitting  off  of 
C02  is  a  normal  reaction  for  cystein,  an  abnormal  reaction  for  lysin  and 
ornithin.  One  might  fancy  that  the  relationship  of  the  cystin  to  the 
ornithin  and  lysin  might  extend  back  into  the  protein  molecule;  but 
they  are  not  related  in  the  protein  molecule,  cystin  being  in  large  part 
early  and  easily  split  off,  lysin  and  arginin  late. 

Histidin. — When  histidin  is  administered  to  dogs,  it  is  burned  and 
the  nitrogen  eliminated  as  urea.  Recent  studies  tend  to  show  that 
the  catabolism  is  accomplished  and  the  ring  ruptured  as  indicated 
in  the  following  equation,  aceto-acetic  acid  being  formed,  later  in  its 
turn  to  suffer  oxidation. 


Histidin 

CH 


Iminazolpyruvic  acid 

CH 


I 
CH 


HN 

I 
C 

CH2     +  O 

CHNH2 

COOH 


HN 


N 

I 
CH 


Aceto-acetic  acid 

CH 


HN        N 


CH2 

I 
CO 


+     2H20 


OC  —  CH3 

=      CH2 

I 
COOH 


I 


OOH 


co2 


+ 
NH3 


The  N-CH-NH  group  isolated  by  the  rupture  of  the  ring  would  form 
urea,  as  would  also  the  ammonia  after  combination  with  the  carbon 
dioxid. 

THE   REST-NITROGEN 


The  partition  of  nitrogen  in  the  urine  is  effected  by  the  quantita- 
tive determination  of  urea,  ammonia,  creatinin,  and  the  purins.  Wlien 
the  sum  of  the  nitrogens  of  these  substances  is  subtracted  from  the 
total  nitrogen  of  the  urine,  the  difference  is  termed  the  rest-nitrogen. 
This  fraction  of  nitrogen  is  only  fairly  constant  in  health,  but  is  in 
particular  more  or  less  independent  of  the  total  nitrogen  input.  In 
this  rest  fraction  are  included  many  different  substances,  and  naturally 
the  amount  may  be  influenced  in  many  different  ways.  For  illustra- 
tion, hippuric  acid  is  included  in  the  rest-nitrogen  and  the  urine  of 
vegetarians  and  fruitarians  is  high  in  rest-nitrogen  on  account  of  the 
large  amounts  of  hippuric  acid  in  their  urine.    It  is,  of  course,  without 


ELIMINA  TION  OF  END  PRODUCTS  OF  PROTEIN  CATABOLISM     417 

clear  purpose  to  group  these  different  substances,  derived  from  many 
sources,  under  one  fraction,  since  it  cannot  be  a  variable  in  itself. 
The  group  is  really  set  apart  because  of  ignorance  of  many  of  the 
constituents. 

The  amount  of  rest-nitrogen  may  vary  from  0.4  or  even  less  to  1.5 
gram  N  per  day.  Since  many  constituents  of  this  fraction  are  derived 
from  the  common  protein,  the  rest-nitrogen  on  a  milk  diet  follows 
roughly  the  urea. 

The  following  substances  are  known  to  be  included  in  the  rest-nitro- 
gen: hippuric  acid;  traces  of  urinary  mucin;  traces  of  diamins;  traces 
of  nitrogenous  phosphatids;  thio-nitrogenous  substances  derived  in  the 
more  or  less  incomplete  oxidation  of  the  sulphur-containing  cystin, 
(included  also  in  the  fraction  of  neutral  sulphur) ;  traces  of  mon-amino- 
acids,  glycocoll  being  most  prominent;  traces  of  polypeptid-like  sub- 
stances including  oxy-proteic  acid,  all-oxy-proteic  acid,  aut-oxy- 
proteic  acid  and  uroferric  acid;  methylguanidin;  allantoin,  urochrome, 
urobilin,  hematoporphyrin,  and  uroerythrin;  and  other  still  less  defined 
nitrogen-containing  substances.  Obviously  this  group  as  a  group 
has  no  meaning  in  metabolism.  The  individual  substances,  of  course, 
have  a  meaning  in  metabolism,  since  they  are  either  end  products, 
eliminated  intermediary  products,  or  bacterial  products.  Individually 
they  are  considered  in  their  appropriate  connections;  as  a  group  they 
possess  no  entity. 


THE  ELIMINATION  OF  THE  END  PRODUCTS  OF  PROTEIN 

CATABOLISM 

Leaving  aside  the  rest-nitrogen,  we  may  regard  the  ammonia  and 
urea  as  representing  the  output  of  the  protein  catabolism.  The  larger 
fraction  goes  out  through  the  urine.  A  certain  fraction  is  eliminated 
in  the  feces.  The  perspiration  contains  under  ordinary  conditions  of 
unconscious  perspiration  from  200  to  300  milligrams  of  nitrogen  per 
day.  With  free  perspiration  that  may  rise  to  as  high  as  a  gram  per 
day.  It  is  clear,  therefore,  that  in  experiments  with  nitrogen  balance, 
particularly  if  the  nitrogen  input  is  low  and  approximating  the  en- 
dogenous demands,  the  fraction  of  nitrogen  eliminated  through  the  skin 
is  not  to  be  neglected.  The  growth  of  the  hair  and  nails  is  a  further 
loss.  A  man  may  lose  as  much  as  100  milligrams  of  nitrogen  per  day  in 
the  growth  of  the  hair.  As  stated  elsewhere,  the  nitrogen  content  of 
the  feces  in  starvation  may  run  from  300  to  500  milligrams  of  nitrogen 
per  day.  Adding  together  these  three  fractions  (perspiration,  intestinal 
excrementation,  and  growth  of  hair  and  nails)  we  are  surprised  to 
realize  that  as  much  as  a  gram  of  nitrogen  may  be  eliminated  per  day 
in  the  extra-renal  output,  and  this  mass  must  always  be  allowed  for  in 
the  interpretation  of  the  facts  of  nitrogenous  metabolism. 

When  the  urea-ammonia  elimination  is  followed  in  hourly  estima- 
27 


418  THE  METABOLISM  OF  PROTEIN 

tions  in  a  subject  on  an  ordinary  mixed  diet  containing  more  or  less 
exogenous  protein,  a  wave  of  elimination  is  observed  that  reaches 
its  maximum  in  from  five  to  seven  hours  after  the  ingestion  of  the 
meal.  The  more  excessive  the  ingestion  of  protein,  the  higher  the 
wave  and  the  more  prolonged  the  downward  stroke  of  the  curve;  with 
massive  ingestions  the  time  required  to  reach  the  crest  of  the  wave 
may  be  deferred  a  couple  of  hours.  If  the  meal  contain  considerable 
fluid,  a  rise  may  be  noted  about  two  hours  after  the  ingestion  of  the 
meal.  This  is  regarded  as  derived  from  stored  nitrogen,  washed  out 
by  the  fluid;  and  this  wave  can  be  provoked  by  the  ingestion  of  water 
alone.  The  second  wave,  about  the  fifth  hour,  represents  the  nitrogen 
of  the  exogenous  catabolism  of  the  meal.  With  the  usual  hours  of 
eating,  it  is  clear  that  the  bottom  of  the  curve  is  not  reached  before 
the  ingestion  of  the  following  meal.  Under  these  circumstances 
the  lowest  point  of  the  curve  is  not  found  until  early  on  the  following 
morning.  It  is  the  exogenous  protein  that  is  largely  responsible  for 
the  sharp  ascent  of  the  curve.  As  the  protein  input  approximates 
more  and  more  the  actual  needs  of  the  body,  the  curve  of  elimination 
approaches  the  straight  line,  with  only  a  slight  rise  after  meals  and 
a  slight  depression  in  the  early  morning.  It  is  a  fair  assumption  that 
the  slight  rise  then  noted  following  meals  is  the  result  of  the  catab- 
olism of  the  amino-acids  of  the  diet  that  are  superfluous  in  the  synthesis 
of  the  blood  proteins.  If,  therefore,  a  dog  were  fed  the  exact  amount 
of  protein  required  by  his  tissues  and  this  input  protein  were  in  the 
form  of  canine  blood  serum,  we  would  expect  the  curve  of  nitrogen 
elimination  to  be  a  practically  straight  line  just  as  the  curve  in  starva- 
tion is  a  practically  straight  line.  A  contemplation  of  the  curves  of 
nitrogenous  elimination  emphasizes  impressively  the  difference  between 
exogenous  and  endogenous  protein  catabolism,  and  leads  to  the  con- 
viction that  the  exogenous  protein  catabolism  is  of  about  as  much  value 
to  the  body  as  is  the  blowing-off  of  steam  to  a  locomotive. 

The  elimination  of  nitrogen  in  the  twenty-four  hours  of  a  day  repre- 
sents in  an  approximate  way  the  input  of  that  day.  This  balance  was 
once  regarded  as  a  rigid  sequence  of  cause  and  effect.  That  it  is  a  rigid 
relation  over  a  long  time  under  controlled  conditions  is  true;  but  it 
does  not  hold  rigidly  for  short  periods.  In  ordinary  balance  experi- 
ments, the  urine  is  collected  from  8  a.m.  to  8  a.m.,  so  that  the  body 
has  fourteen  hours  in  which  to  complete  the  catabolism  of  the  protein 
of  the  evening  meal.  But  the  day-after-day  figures  for  the  nitrogen 
output  will  be  found  to  fluctuate  rather  markedly  in  a  subject  on  a 
constant  input.  If  the  daily  input  be  15  grams  of  nitrogen,  the  output 
may  fluctuate  from  13  to  17  grams;  the  fluctuations  are  irregular  but 
in  the  long  run  compensatory.  For  several  days  the  daily  balance  may 
be  perfect ;  then  for  a  few  days  the  output  may  lag  behind  several  grams 
per  day;  following  this  for  successive  days  the  output  will  be  several 
grams  in  excess  of  the  input.  Temporary  retention  is  the  cause  of  this 
fluctuation;  there  is  a  lagging,  followed  by  a  sweeping-out  until  the 


ELIMINATION  OF  END  PRODUCTS  OF  PROTEIN  CATABOLISM     419 

balance  is  attained.  Occasionally  this  may  involve  as  much  as  one- 
fourth  of  the  nitrogen  input.  It  is  different  in  different  individuals, 
and  is  most  marked  in  subjects  on  a  liberal  input  of  protein.  The 
fluctuations  have  sometimes  a  relation  to  the  total  volume  of  the 
urine  (tending  to  rise  with  polyuria),  but  none  to  any  apparent  factor 
in  digestion  or  mode  of  life. 

It  is  important  to  know  whether  this  lagging  is  in  the  catabolism 
or  in  the  elimination.  If  such  lags  occur  in  the  protein  catabolism, 
we  might  expect  more  marked  lags  to  occur  under  pathological  condi- 
tions. If  the  lags  are  located  in  the  function  of  elimination,  we  might 
expect  more  marked  lags  to  occur  in  pathological  conditions  involving 
especially  the  renal  system.  There  are  today  no  data  upon  which  a 
decision  of  this  question  may  be  based.  If  a  lag  in  the  protein  catab- 
olism occurred  prior  to  the  stage  of  deaminization,  we  might  expect, 
under  very  careful  conditions  of  experimentation,  to  detect  it  by  the 
estimation  of  the  respiratory  quotient.  The  more  natural  assumption 
a  priori  is  that  the  lag  is  in  the  elimination.  But  when  we  attempt 
to  test  this  interpretation  in  practice,  it  is  very  doubtful  if  it  proves 
valid.  We  know  of  three  conditions  in  which  similar  lags  occur  fre- 
quently. In  protein  overfeeding,  the  nitrogen  output  may  fall  behind 
the  input.  Some  times,  particularly  in  young  adults,  this  retention 
is  permanent,  and  corresponds  to  a  true  retention  in  flesh.  But  more 
often,  when  the  overfeeding  is  discontinued  the  retained  nitrogen  is 
gradually  eliminated  in  the  urine,  so  that  after  a  number  of  days  the 
extra  protein  of  the  input  is  balanced  by  the  excess  nitrogen  of  the 
urine.  Under  these  circumstances,  was  the  lag  in  the  catabolism  or 
in  the  elimination?  The  amount  of  carbohydrate  in  the  diet  has  a 
definite  effect  in  the  production  of  nitrogen  lag.  When  glycocoll  or 
asparagin  are  administered  to  a  dog,  it  can  be  shown  that  the  elimina- 
tion of  the  nitrogen  is  definitely  retarded,  so  much  so  as  to  have  led 
to  the  suggestion  that  possibly  amino -sugars  were  formed  under  such 
circumstances.  In  chronic  nephritis,  apart  from  any  visible  dropsy 
(as  in  arteriosclerotic  nephritis  with  polyuria),  one  may  observe  a  lag 
in  the  nitrogen  output  extending  over  a  number  of  days,  followed  by 
a  sweeping-out.  Here  the  lag  is  independent  of  the  input.  Was  the 
lag  in  the  catabolism  of  protein  or  in  the  elimination  ?  In  the  continued 
fevers,  best  seen  perhaps  in  typhoid  fever,  the  patient  usually  on  a 
low  protein  input  may  appear  to  be  in  nitrogen  equilibrium  during 
the  febrile  period  of  the  disease.  Following  the  defervescence  of  the 
fever,  in  association  with  a  post-febrile  diuresis  or  independent  of  it, 
a  large  amount  of  urea  may  be  eliminated.  Was  this  stored  in  the 
body  in  defect  of  elimination,  was  uncatabolized  protein  stored  in  the 
body  during  the  febrile  period;  or  was  there  a  large  post-febrile  catab- 
olism of  tissue  protein?  It  seems  clear,  unsatisfactory  as  it  may  be, 
that  no  explanation  will  fit  all  these  various  sets  of  circumstances  and 
the  lags  that  are  observed  with  normal  subjects  on  normal  diets.  When 
one  considers  the  great  solubility  of  urea  and  the  ease  with  which  the 


420 


THE  METABOLISM  OF  PROTEIN 


kidney  eliminates  urea  administered  parenterally,  it  seems  far-fetched 
to  regard  these  lags  as  due  to  defective  elimination.  When,  on  the 
other  hand,  one  contemplates  the  almost  boundless  power  of  catabolism 
of  common  protein  possessed  by  the  tissues,  including  the  formation 
of  urea  from  ammonium  salts,  it  seems  far-fetched  to  attribute  the 
lags  to  defective  catabolism.  States  of  storage  of  either  protein,  amino- 
acids  or  of  urea  are  not  easily  assumed,  though  possible — protein  pre- 
senting the  least  difficulty  in  this  regard.  The  occurrence  of  dropsy 
cannot,  of  course,  be  excluded,  since  the  body  can  retain  several  liters 
of  water  without  the  slightest  external  sign,  and  it  is  very  difficult 
by  the  control  of  the  body  weight  or  measurements  of  water  input  and 
output  to  even  approximately  establish  a  water  balance.  But  it  does 
not  seem  possible  to  assume  dropsy,  physiological  or  pathological, 
for  these  retentions.  A  lag  is  surely  present  in  either  catabolism  or  in 
elimination. 

The  following  scheme  illustrates  the  main  facts  of  the  protein  metab- 
olism, including  exogenous  protein. 


Input 


Blood 


Superfluous 
aruino-acids 


Metabolism 


Output 


Amino-acids 


-Greatinine 


-Uric  acid 


Pur  in  bases 


THE   METABOLISM   OF   SULPHUR 


On  account  of  its  intimate  relations  to  the  protein  metabolism,  the 
metabolism  of  sulphur  possesses  peculiar  interest.  Despite  the  fact 
that  we  are  dealing  with  an  inorganic  substance,  we  are  still  far  from 


THE  METABOLISM  OF  SULPHUR  421 

a  comprehensive  view  of  the  details  of  the  metabolism  of  sulphur. 
Sulphur  exists  in  the  diet  in  both  organically  combined  and  in  inorganic 
state.  So  far  as  known,  the  inorganic  sulphur  of  the  diet  has  no  impor- 
tance for  the  processes  of  metabolism.  Inorganic  sulphur  cannot  be 
utilized  in  the  body  for  the  synthesis  of  the  sulphur  combined  in  pro- 
tein, this  must  be  ingested  preformed.  Sulphur  exists  in  organic  combi- 
nation in  some  of  the  fats  of  foods,  but  so  far  as  known  this  sulphur 
is  completely  oxidized  in  the  body,  and  is  not  utilized  for  organic 
combination.  From  all  the  available  data,  the  only  sulphur  required 
in  the  diet  is  the  sulphur  combined  in  protein;  the  sulphur  combined 
in  fats  is  oxidized  and  the  inorganic  sulphur  merely  passes  through 
the  system.  The  sulphur  combined  in  protein  is  largely  if  not  entirely 
in  the  di-thio-amino-acid,  cystin.  This  substance  is  absolutely  indis- 
pensable to  nutrition,  and  it  cannot  be  formed  in  the  body  of  the 
higher  animal.  A  normal  and  competent  protein  ration  must,  there- 
fore, include  such  proteins  as  contain  the  sulphur-bearing  amino-acid 
in  ample  quantity.  When  the  proteins  are  digested  the  cystin  is  re- 
sorbed  unchanged,  to  become  an  integral  component  of  the  different 
proteins  synthesized  in  the  reactions  of  protein  anabolism.  From 
cystin  apparently  are  derived  by  complex  synthesis  the  sulphured  lipoids 
that  are  present  in  the  central  nervous  system,  in  the  bile  and  in  the 
secretions  of  the  cutaneous  system. 

The  outlets  of  sulphur  are  three:  in  the  urine,  in  the  stools,  and  in 
the  cutaneous  secretions.  The  amount  of  sulphur  eliminated  through 
the  skin  is  considerable,  about  30  milligrams  of  sulphur  per  day.  The 
sulphur  of  the  stools  consists  of  three  fractions  apart  from  ingested 
inorganic  salts;  the  sulphur  compounds  of  the  bile;  the  sulphur-contain- 
ing mucin  of  the  alimentary  secretions;  and  the  sulphur  of  the  undi- 
gested or  unresorbed  protein  of  the  diet,  more  or  less  modified  by  bacterial 
action.  To  these  must  be  added  the  sulphur  of  the  bacterial  bodies. 
It  is  not  analytically  possible  to  separate  these  fractions.  The  sulphur 
content  of  the  stools  varies  from  0.2  to  0.3  gm.  per  day.  The  sulphur 
compounds  of  the  bile  were  described  under  that  heading.  It  is  not 
known  to  what  extent  these  substances  are  discharged  in  the  feces,  to 
what  extent  they  are  digested  or  acted  upon  by  bacteria  in  the  intestine, 
or  in  how  far  they  may  be  resorbed. 

The  sulphur  fractions  of  the  urine  are  three:  neutral  sulphur,  pre- 
formed sulphates,  and  ethereal  or  conjugated  sulphates.  The  last  is 
really  only  a  portion  of  the  preformed  sulphates,  conjugated  with 
phenols,  cresols,  indols,  skatols  and  their  derivatives.  Whatever 
amount  of  these  substances  (the  products  of  bacterial  action  on  amino- 
acids  in  the  intestine)  is  resorbed,  this  is  in  the  liver  conjugated  with 
sulphuric  acid,  the  amount  of  the  preformed  sulphates  being  by  that 
much  reduced.  It  is  not  possible  for  so  much  of  these  aromatic  bodies 
to  be  formed  as  to  entirely  appropriate  the  sulphate  of  the  same  period. 
Metabolically  the  ethereal  sulphates  have  the  same  meaning  as  the 
preformed  sulphates.     In  general,  the  oxidized  sulphur  corresponds  to 


422  THE  METABOLISM  OF  PROTEIN 

the  urea  nitrogen,  or  better,  to  that  fraction  of  the  urea  nitrogen  that 
is  derived  from  the  catabolism  of  exogenous  protein.  It  is  tempting 
to  relate  this  fraction  of  sulphur  solely  to  the  exogenous  protein,  but 
the  data  are  not  yet  sufficiently  extensive  to  warrant  this  conclusion. 

The  neutral  sulphur  is  a  constant  for  each  individual,  being  closely 
parallel  to  the  nitrogen  of  the  endogenous  catabolism  of  protein,  inde- 
pendent of  the  exogenous  catabolism  of  protein.  Here,  again,  it  is 
tempting  to  relate  this  fraction  solely  to  the  endogenous  protein,  but 
the  analytical  data  are  too  meagre.  As  an  hypothesis,  however,  it  has 
proper  claims  to  our  attention. 

Theoretically  there  should  be  a  balance  in  the  sulphur  metabolism. 
Analytically  it  is  not  possible  to  establish  such  a  balance.  This  is  due 
to  difficulties  in  determining  the  sulphur  eliminated  by  the  skin,  and 
to  inaccuracies  in  the  methods  used  for  the  estimation  of  the  total 
sulphur  of  the  foodstuffs  and  feces. 

Our  knowledge  of  pathological  variations  in  the  sulphur  metabolism 
is  very  limited  and  fragmentary.  Cystinuria,  an  interesting  anomaly 
of  the  protein  catabolism,  has  been  described  under  that  heading. 


CHAPTER    VII 

METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

THE  METABOLISM  OF  CREATIN-CREATININ 

Creatin  is  methylguanidin-acetic  acid.    The  structures  of  guanidin, 
of  creatin,  and  of  its  anhydrid  creatinin  are  as  follows: 

Guanidin  Creatin  Creatinin 

NH2  NH2  COOH         NH— CO 


/  / 

C  =  NH       C  =  NH 


C  =  NH 


NH2 


CH3 


I 
(CH.) 


The  relationship  of  guanidin  to  urea  is  obvious: 

NH2  NH2 

/  / 

.  C=0  C  =  NH 

\  \ 

NH2  NH2 

Urea  is  easily  formed  from  guanidin  by  oxidation,  it  is  indeed  from 
a  guanidin  rest  that  urea  is  formed  from  arginin  by  arginase. 

The  subject  matter  of  this  metabolism  is  in  a  state  of  confusion, 
owing  to  numerous  contradictions  in  work  done  with  different  or  even 
with  the  same  methods,  and  a  survey  of  the  metabolism  is  very  difficult. 
To  the  author  it  seems  that  the  following  presentation  contains  the 
best  interpretation  of  the  most  clearly  established  or  least  contradicted 
findings. 

Elimination  of  Creatinin. — The  elimination  of  creatinin,  as  related 
to  its  formation,  is  for  each  individual  a  constant  related  to  the  mass 
of  muscular  tissue,  representing  the  coefficient  of  muscular  metabolism; 
independent  of  the  formation  of  urea  (into  which  it  may  be  converted) 
or  of  the  partition  of  urinary  nitrogen;  independent  of  the  endogenous 
or  exogenous  catabolism  of  protein;  independent  of  the  protein  input 
when  flesh  is  excluded.  If  an  animal  be  fed  a  nitrogen-free  diet  con- 
taining carbohydrate  and  salts  in  proper  amounts,  the  urinary  nitrogen 
will  after  a  time  maintain  a  constancy  in  output  and  partition  which 
represents  the  minimal  endogenous  nitrogenous  catabolism.  Under 
such  circumstances  (tests  in  swine  have  given  very  clear  results),  the 


424      METABOLISM  OF  CREATIN-CREATIN1N  AND  OF  PURIN 

nitrogen  output  varies  from  0.025  to  0.035  gram  nitrogen  per  kilo  per 
day.  About  18  per  cent,  of  this  is  creatinin  nitrogen  (endogenous 
creatinin),  and  the  figure  is  very  constant;  urea  nitrogen  is  about 
60  per  cent. 

There  is  this  endogenous  and  also  a  possible  exogenous  fraction  of 
creatinin  in  the  urine,  and  therefore  an  endogenous  and  an  exogenous 
metabolism.  The  endogenous  metabolism  of  these  substances  is  an 
especial  cellular  metabolism,  localized  in  the  muscles.  This  is  made 
clear  by  its  independence  of  conditions  of  increased  tissue  catabolism 
outside  of  the  muscles,  as  in  the  exaggeration  of  hepatic  catabolism 
that  occurs  in  starving  dogs  poisoned  with  phosphorus.  The  exogenous 
fraction  is  derived  from  flesh  in  the  diet.  It  is  not  derived  from  the 
protein  of  the  diet,  but  from  the  flesh  of  the  diet.  Meat  contains  one 
or  two  parts  of  creatin  in  the  thousand.  Meat  extracts  contain  com- 
bined creatin.  On  cooking,  creatin  is  set  free  and  some  creatinin  is 
formed.  It  is  these  so-called  extractive  elements  that  form  the  exog- 
enous creatinin  fraction.  Otherwise,  the  creatinin  is  independent 
of  the  protein  of  the  diet;  it  is  one  of  the  most  constant  eliminations, 
and  in  every  way  behaves  like  the  end  product  of  a  specific  metabolism, 
just  as  do  the  purins.  There  are  moderate  variations  in  the  creatinin 
outputs  of  different  individuals;  but  in  the  same  individual,  if  exog- 
enous creatinin  be  excluded,  the  elimination  is  remarkably  constant 
(about  0.02  gram  per  kilo)  and  independent  of  the  common  protein 
metabolism. 

Derivation  of  Creatin. — The  creatin  exists  in  the  muscles  in  a  non- 
dialyzable  state  of  combination,  in  some  complex'  in  the  muscle  plasma. 
Whence  is  this  creatin  derived?  When  one  realizes  that  the  sole  pre- 
formed guanidin,  known  at  least,  is  in  the  molecule  of  arginin  and  that 
this  is  converted  into  urea  by  arginase,  one  is  led  to  regard  the  presence 
of  creatin  in  the  muscle  plasma  as  an  act  of  synthesis.  Regarded  in 
this  way,  we  would  term  creatin  a  special  anabolic  product  of  the 
muscle  cell,  formed  de  novo  from  protein  by  synthesis  and  deposited 
in  the  muscle  plasma.  In  what  condition  of  combination  creatin 
exists  in  the  muscle  plasma  is  not  known.  A  complex  recently  isolated 
from  meat  extract  offers  a  suggestion  in  this  direction.  This  substance, 
termed  vitiatin,  has  the  composition: 

NH2 

/ 
C  =  NH  NH2 

N(CH3).CH2.CH2.NH.C  =  NH 

This  is  obviously  a  combination  of  guanidin  with  amino-acid,  and 
suggests  that  in  muscle  protein  there  is  a  special  polypeptid-like  combi- 
nation of  creatin  with  amino-acid.  It  is  a  striking  fact  that  guanidin 
(creatinin)  is  recovered  most  largely  in  the  autolysis  of  muscle. 

What  are  we  to  regard  as  the  mother  substance  of  creatin?  The 
amino-acids  would  most  naturally  be  looked  upon  as  the  probable 


THE  METABOLISM  OF  CREATIN-CREAT1NIN  425 

source.  Guanidin  acetic  acid  is  in  the  rabbit  converted  into  creatin 
by  the  addition  of  a  methyl  group.  This  observation,  however,  does 
not  help  us  much,  for  we  are  not  able  to  trace  the  way  from  ami  no- 
acid  to  guanidin.  Another  view  is  that  creatin  is  formed  from  creatinin 
in  the  liver,  and  then  conveyed  to  the  muscles.  This  hypothesis  has 
little  experimental  evidence  in  its  favor,  though  there  is  evidence  tend- 
ing to  show  that  the  relation  creatin  <  =  >  creatinin  is  reversible.  In 
favor  of  this  view  may  be  also  the  fact  that  when  creatin  is  administered 
to  an  animal  or  man,  it  is  partly  eliminated  and  partly  retained.  By 
retained  one  could  understand  conveyed  to  the  muscle  (as  a  food), 
just  as  the  creatin  assumed  to  have  been  synthesized  from  creatinin 
in  the  liver  would  be  conveyed  to  the  muscles.  This  explanation  in  any 
event  only  puts  the  problem  back  one  step,  for  whence  is  the  creatinin 
derived?  We  are  not  dependent  on  exogenous  creatinin.  If  creatinin 
be  the  parent  substance  of  creatin,  what  is  the  parent  substance  of 
creatinin?  To  the  writer,  however,  the  derivation  of  creatin  from 
amino-acids  seems  much  the  more  reasonable  assumption. 

The  creatin  in  the  muscle  plasma  is  therefore  regarded  as  the  parent 
substance  of  the  creatinin  of  the  urine.  This  conversion  we  regard 
as  due  to  ferment  action,  representing  a  special  catabolism  of  the 
muscle  cell.  Autolytic  experiments  have  made  such  formation  of 
creatinin  from  creatin  in  muscle  very  probable.  This  formation  of 
creatinin  from  creatin  is  a  part  of  the  life  of  the  muscle  cell,  not  a 
result  of  its  function  of  contraction.  Normal  muscular  movements 
are  not  associated  with  any  increase  in  the  elimination  of  creatinin. 
Only  when  the  muscle  is  untrained  or  the  exertion  is  excessive  and 
accomplished  without  food,  is  the  elimination  of  creatinin  increased  by 
muscular  movements.  The  heart  beating  in  artificial  solutions,  however, 
gives  off  creatinin  to  the  solution.  Electrical  tonus,  rigor  caloris,  and 
rigor  mortis  result  in  increased  formation  of  creatin-creatinin. 

Administration  of  Creatin. — When  creatin  is  administered  it  is  partly 
retained  (as  food  or  destroyed),  and  partly  eliminated  unchanged; 
a  small  amount  is  converted  into  creatinin.  The  result  of  this  experi- 
ment need  not  speak  against  the  derivation  of  creatinin  from  creatin 
in  the  muscle  cell.  It  is  possible  that  this  is  a  special  catabolism  of 
the  muscle  cell,  that  creatin  free  in  the  circulating  fluids  does  not 
meet  the  particular  conditions  necessary  for  this  reaction  and  present 
only  in  the  muscle  cell.  It  is  clear  that  this  experiment  is  one  in  which 
a  positive  result  proves  but  a  negative  result  does  not  disprove.  Tests 
by  administration  of  creatin  by  mouth  are  not  to  be  trusted,  as  creatin 
is  subject  to  bacterial  disintegration  in  the  alimentary  tract.  Paren- 
ternal  introduction  alone  is  to  be  relied  upon,  and  the  majority  of 
tests  with  this  method  have  given  a  positive  result,  a  certain  fraction 
of  creatin  appears  as  creatinin.  When  creatinin  is  introduced,  it  is 
mostly  eliminated  unchanged,  a  small  fraction  is  apparently  converted 
into  urea. 

The  daily  output  of  creatinin  may  rarely  be  as  low  as  1  gram  or  as 


426     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

high  as  2  grams;  average  figures  run  from  1.3  to  1.7  for  different  individ- 
uals. The  values  are  naturally  less  fluctuating  when  the  exogenous 
creatinin  is  excluded,  as  this  is  largely  eliminated  unchanged.  In  one 
individual  it  is  common  to  see  the  elimination  of  creatinin  (endogenous 
creatinin)  vary  no  more  than  50  milligrams  from  day  to  day.  Creatin 
is  not  usually  present  in  the  urine.  In  birds  creatin  replaces  creatinin 
in  the  urine.  Creatin  is  normally  present  in  the  urine  of  sucklings 
and  also  of  children.  At  what  age  of  the  child  it  ceases  to  appear  and 
whether  its  occurrence  is  at  all  dependent  on  the  diet,  must  be  deter- 
mined by  future  investigations. 

Creatinin  Metabolism,  a  Special  Metabolism. — The  cardinal  feature 
of  this  theory  of  the  metabolism  lies  in  the  definition  of  the  creatinin 
metabolism  as  a  specific  metabolism.  Just  as  we  believe  that  purin 
and  pyrimidin  are  synthesized  from  protein  and  later  bound  in  the 
molecule  of  nuclein,  from  thence  on  to  constitute  a  specific  metabolism, 
independent  of  the  metabolism  of  common  protein;  so  we  assume 
that  creatin  is  synthesized  from  protein,  directly  or  indirectly,  and 
combined  in  the  muscle  plasma,  from  thence  on  to  constitute  a  specific 
metabolism,  independent  of  the  common  protein  metabolism.  Here 
we  have  limited  the  role  of  creatin  to  the  muscular  system.  Possibly 
this  may  be  a  mistake.  It  is  true  that  other  cells  than  muscle  contain 
traces  of  creatin;  and  cells  other  than  muscle  will  form  creatinin  from 
creatin  on  autolysis.  But  the  trace  of  creatin  in  other  cells  is  so  small, 
contrasted  with  the  amounts  present  in  the  muscles,  that  it  seems 
certain  that  we  must  accord  to  the  muscular  system  a  particular  impor- 
tance in  this  metabolism,  if  not  the  exclusive  role.  Future  investigations 
will  determine  this  relation. 

Creatinin  an  Endogenous  Source  of  Urea. — Creatinin  is  one  of  the 
endogenous  sources  of  urea.  It  is,  however,  very  difficult  to  form 
an  estimate  of  the  amount  thus  transformed  into  urea.  No  direct 
method  is  available.  If  we  administer  to  a  man  an  amount  of  creatinin 
equal  to  the  maximum  amount  in  the  urine,  2  grams,  it  will  be  found 
that  from  three-fourths  to  four-fifths  will  be  eliminated  unchanged, 
the  balance  will  apparently  have  been  converted  into  urea.  0.4  gram 
of  creatinin  corresponds  to  0.36  urea;  while  this  is  a  large  portion  of 
the  creatinin  it  is  a  small  fraction  of  urea.  Such  an  assumption,  rest- 
ing upon  the  supposition  that  the  reaction  with  a  certain  amount  of  a 
substance  administered  by  the  mouth  will  be  the  same  as  though  that 
substance  had  originated  in  the  intermediary  metabolism,  is,  of  course, 
very  insecure.  But  it  is  the  only  indirect  way  of  attempting  to  form 
an  idea  of  the  formation  of  urea  from  creatinin  in  the  body.  The 
constancy  of  urinary  creatinin  indicates  that  whatever  the  degree  of 
transformation  into  urea,  this  and  the  formation  of  creatinin  from 
creatin  must  both  be  regarded  as  processes  of  striking  uniformity. 

The  urine  contains  traces  of  methylguanidin  and  dimethylguanidin, 
that  are  to  be  attributed  to  the  catabolism  of  creatinin  (or  creatin) 
either  in  the  metabolism  or  in  the  alimentary  tract. 


THE  METABOLISM  OF  CREATIN-CREATININ  427 

Pathological  Variations  of  Metabolism. — The  pathological  variations 
in  the  metabolism  of  creatin  and  creatinin  have  lately  attracted  much 
attention,  and  are  unquestionably  of  great  importance.  These  varia- 
tions are  in  one  of  two  directions:  in  the  direction  of  excess  or  reduc- 
tion in  the  elimination  of  creatinin,  creatin  being  absent;  or  in  the 
elimination  of  creatin  at  the  expense,  so  to  speak,  of  creatinin.  The  data 
bearing  on  the  increase  or  decrease  in  the  total  elimination  of  creatinin 
in  conditions  of  disease  are  more  or  less  dubious  on  account  of  the 
fact  that  the  diets  have  usually  not  been  controlled  and  exogenous 
creatin  and  creatinin  excluded.  Nevertheless,  it  is  probable  that  the 
total  elimination  may  be  increased  under  certain  conditions  of  rapid 
degeneration  and  wasting  of  the  muscular  substance.  Such  an  occur- 
rence with  high  fever  or  following  prolonged  exposure  to  high  external 
temperature  may  be  attributed  to  muscular  degeneration.  On  the 
contrary,  late  in  the  progressive  muscular  dystrophies,  the  elimina- 
tion seems  to  be  lowered.  It  should  be  pointed  out  that  estimations 
in  states  of  disease  must  reveal  striking  deviations,  as  individualities 
in  creatinin  elimination  are  rather  marked.  It  must  also  be  determined 
that  the  diet  is  creatin-creatinin-free,  and  contains  an  ample  input  of 
carbohydrate  as  well  as  protein.  The  weight  of  the  individual  must 
likewise  be  taken  into  account,  since,  as  a  rule,  the  elimination  of  crea- 
tinin is  proportional  to  the  muscular  development  or  muscular  stature 
of  the  individual,  fat  and  thin  subjects  presenting  lower  elimination. 

More  interesting,  at  present  at  least,  are  the  findings  of  creatin  in 
the  urine  in  states  of  disease.  In  accordance  with  the  interpretation 
of  this  metabolism  here  adopted,  the  appearance  of  creatin  is  usually 
to  be  regarded  as  an  instance  of  arrested  transformation;  instead  of 
being  converted  into  creatinin,  creatin  issues  unchanged.  It  is  now 
definitely  known  that  the  muscle  cells  may  synthesize  creatin  in  excess; 
there  is  in  fact  evidence  tending  to  ehow  that  in  starvation  the  forma- 
tion of  creatin-creatinin  is  always  above  normal.  But  if  such  over- 
production of  creatin  does  occur  also  in  pathological  states,  future  studies 
will  need  to  fix  such  occurrence;  we  shall  here  assume  the  appearance 
of  creatin  in  disease  to  be  at  the  expense  of  creatinin.  In  three 
groups  of  conditions  especially  is  creatin  to  be  found  in  the  urine. 
(a)  In  inanitions,  no  matter  what  the  cause,  be  it  starvation,  chronic 
infectious  disease,  neoplasmic  cachexia,  intractable  vomiting  as  in 
pregnancy,  exophthalmic  goitre,  etc.  The  explanation  to  be  offered  in 
these  cases  is  that  muscle  is  being  catabolized  to  support  the  glandular 
and  nervous  systems.  If  the  carbohydrate  input  be  normal  in  these 
cases,  creatin  may  not  appear  in  the  urine;  if  it  be  deficient,  creatin 
does  appear.  (6)  In  acute  and  rapid  degeneration  of  muscle  tissue,  such 
as  is  to  be  seen  in  muscular  neoplasms,  in  dystrophies,  in  connection 
with  myelitis,  following  prolonged  exposure  to  extreme  heat,  during 
the  involution  of  the  uterus  in  the  puerperium,  in  short,  whenever 
muscle  undergoes  rapid  disintegration.  The  explanation  here  to  be 
offered  is  that  it  is  in  the  functionating  muscle  cell  that  the  conversion 


428     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

of  creatin  to  creatinin  occurs;  when  the  cells  degenerate,  the  creatin 
is  set  free  and  passes  in  the  circulation  to  the  kidneys,  (c)  In  con- 
nection with  suboxidation  of  glucose.  Recent  evidence  tends  to  indicate 
that  the  combustion  of  glucose  bears  to  the  conversion  of  creatin  into 
creatinin  the  same  relation  it  often  bears  to  the  combustion  of  butyric 
acid;  the  reaction  is  in  some  way  rendered  incomplete  without  it. 
When  there  is  little  sugar  burned  (either  because  the  body  has  no  glucose 
to  burn  or  cannot  burn  it)  creatin  is  eliminated,  just  as  are  the  ketonic 
acids.  In  diabetes  and  in  phloridzin  poisoning  creatin  appears  in  the 
urine.  Obviously,  many  of  the  above  instances  cited  under  (a)  and 
(6)  may  in  reality  have  been  due  to  the  absence  of  sugar  combustion. 
It  may  be  experimentally  shown  that  creatin  elimination  in  nitrogen 
starvation  is  checked  by  the  administration  of  carbohydrate,  but 
continues  with  the  administration  of  an  isodynamic  ration  of  fat. 
Future  investigations  will  have  to  determine  the  exact  relations  in 
these  three  groups  of  cases,  both  as  to  facts  and  as  to  their  interpreta- 
tion. In  the  literature  much  emphasis  has  been  laid  upon  the  occur- 
rence if  creatin  in  organic  diseases  of  the  liver,  as  in  carcinoma,  cirrhosis, 
chloroform  degeneration,  phosphorus  poisoning  and  in  eclampsia. 
These  cases  might  be  ranged  under  one  of  the  three  groups;  possibly 
it  may  be  through  disturbances  in  the  glycogenetic  function  of  the 
liver  that  the  occurrence  of  unconverted  creatin  is  to  be  explained. 
The  non-importance  of  the  liver  itself  in  the  occurrence  of  creatin  in 
the  urine  is  shown  by  the  fact  that  dogs  with  Eck  fistula  react  just 
as  do  normal  dogs,  which  is  scarcely  to  be  reconciled  with  the  idea  of 
a  predominating  influence  on  the  part  of  that  organ.  The  recently 
published  statement  that  creatin  is  a  normal  constituent  of  the  urine 
during  pregnancy  demands  confirmation  under  rigid  conditions  of 
control. 

THE   PURIN'  METABOLISM 

Structure  of  Nucleic  Acid. — The  protein  metabolism  may  be  defined 
in  general  terms  as  the  metabolism  of  protoplasm.  The  nucleic  metab- 
olism we  regard  in  the  same  general  way  as  the  metabolism  of  the 
nucleus.  The  nucleus  contains,  of  course,  protoplasmic  protein:  and 
nucleoproteins  exist  outside  of  nuclei.  But  it  is  especially  with  the  basic 
substances  of  the  nucleus,  the  chromatin,  that  the  nucleic  metabolism 
is  concerned.  This  has  a  totally  different  structure  and  composition: 
its  metabolism  is  a  function  sui  generis,  always  to  be  regarded  as 
independent  of  the  metabolism  of  common  protoplasm.  While  many 
of  the  details  of  the  nucleic  metabolism  have  been  long  known,  it  has 
been  but  lately  that  our  knowledge  of  the  chemical  structure  of  nucleic 
acid  has  been  developed  to  such  a  point  as  to  enable  one  to  make  a 
survey  of  the  field. 

The  nucleoproteins  are  perhaps  the  most  widespread  of  the  com- 
pound or  conjugated  proteins.  Existing  in  every  organ  and  tissue, 
they  vary  widely,  depending  upon  differences  in  the  nucleic  fraction. 


THE  PURIN  METABOLISM  429 

The  proteins  with  which  the  nucleic  acids  are  combined  in  the  different 
organs  and  tissues  are  most  often  to  be  defined  as  of  the  globulin  type. 
But  as  globulins  vary  from  organ  to  organ  and  from  tissue  to  tissue, 
it  were  a  mistake  to  attribute  the  variations  in  nucleoproteins  entirely 
to  the  nucleic  fraction.  It  is,  however,  the  variations  in  the  nucleic 
fraction  that  are  most  striking;  the  variations  in  the  globulins,  in  the 
chemical  sense  at  least,  are  very  much  less  prominent.  The  structure 
of  nucleoprotein  is  generally  stated  to  be  as  follows: 

Nucleoprotein 


Globulin  Nuclein 


Globulin  Nucleic  acid. 


The  amphoteric  protein  acts  as  base,  the  nucleic  acids  are  rather  strongly 
acid.    This  is  not  the  only  form.    Thus  we  may  have: 

Nucleoprotein 


Globulin  Nuclein 


Histon  Nucleic  acid. 


Histon-nucleic  acid  and  protamin-nucleic  acid  occur  also  in  nature  as 
such,  not  combined  with  higher  protein  to  form  nucleoproteins.  Combi- 
nations with  albumin  also  occur.  It  seems  clear  that  nucleoproteins 
differ  from  nucleins  in  the  matter  of  the  second  molecule  of  protein. 
One  might  define  them  as  simple  and  compound  nucleins. 

Nucleic  acids  are  compounds  of  phosphoric  acid  with  sugar  and  an 
organic  base.  The  sugar  is  always  a  pentose;  the  base  either  a  purin 
or  a  pyrimidin.  The  best  nomenclature  has  been  evolved  from  experi- 
mental work;  and  since  it  gives  the  most  clear-cut  ideas  of  definition, 
we  will  abandon  the  older  terms.  Under  nucleosids  we  understand 
a  glucosid-like  combination  of  pentose  with  the  purin  or  pyrimidin 
base;  we  have,  therefore,  purin  nucleosids  and  pyrimidin  nucleosids. 
Under  the  term  nucleotid  we  understand  the  complex  formed  by  the 
union  of  phosphoric  acid  with  a  nucleosid.  Nucleic  acids  as  they  occur 
in  nature  are  mono-  or  polynucleotids.  Mononucleotids  and  tetra- 
nucleotids  are  definitely  known;  the  most  common  of  the  tissue  nucleic 
acids  are  tetranucleotids.  But  there  can  be  no  doubt  that  di-  and 
possibly  trinucleotids  may  exist;  and  even  more  groups  than  four 
possibly  occur  in  combination.  The  polynucleotids  seem  always  to 
contain  both  purin  and  pyrimidin  nucleosids.  In  the  polynucleotids 
the  bindings  between  the  several  nucleotids  are  effected  with  the 
oxygen  and  phosphorus  of  the  phosphoric  acid  molecules.  In  each  of 
these  combinations  water  is  extruded;  and  conversely  their  cleavage 
is  a  reaction  of  hydrolysis.    Thus: 

Purin  +  pentose  =  nucleosid  +  water 

Nucleosid  +  phosphoric  acid  «-  nucleotid  +  water 


430     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

The  purin  nucleosids  are  far  better  understood  than  the  pyrimidin 
combinations. 

The  purin  nucleosids  are  three  in  number,  depending  on  which  purin 
base  is  present.  The  combination  of  adenin  with  the  pentose  is  termed 
adenosin;  the  combination  of  guanin  with  the  pentose  is  termed  guanosin; 
and  the  combination  of  hypoxanthin  with  the  pentose  is  termed  inosin. 
Xanthin  so  far  as  known  does  not  exist  combined  preformed  in  a 
nucleosid.  Nor  are  any  of  the  methyl  purins,  frequently  found  in 
nature,  known  to  exist  in  the  nucleosids  of  plants. 

Recent  studies  of  the  nucleosids  indicates  that  the  pentose  in  the 
known  nucleosids  of  plant  and  animal  origin  is  d-ribose;  d-ribose  has 
the  stereoisomeric  equation : 

COH 


HO 
HO 
HO 

h. 


OH 
OH 
OH 
H2OH 


The  results  of  earlier  investigations,  according  to  which  the  pentose  in 
nucleic  acids  was  1-xylose  or  an  arabinose,  have  apparently  been  revised 
to  the  effect  that  the  pentose  in  the  known  nucleosids  is  d-ribose. 
They  are  therefore  ribosids. 

There  are  three  pyrimidins  occurring  in  nucleosids;  and  corresponding 
to  the  purin  ribosids  we  may  assume  that  in  different  nucleic  acids 
exist  thymin  ribosid,  cytosin  ribosid  and  uracil  ribosid.  These  nucleo- 
sids have  not  been  isolated  and  studied  with  the  attention  given  to 
the  purin  ribosids. 

The  combination  of  purin  with  ribose  to  form  the  nucleosids  may 
be  illustrated  as  follows: 

CHO  HC-^— -    -C5H4N5O 


HCOH 


HCOH^ 


\ 


HCOH         +        C5H5N60         =         HCOH        ^O       +     H20 


H^- 


I 

HCOH 

CH2OH  HC2OH 

It  is  known  that  the  purin  is  attached  to  the  carbon  of  the  aldehyd 
group,  but  we  do  not  know  where  in  the  purin  the  attachment  is  effected. 
Theoretical  considerations,  however,  suggest  that  the  attachment 
may  be  at  7. 

The  combination  of  the  nucleosid  with  phosphoric  acid  to  form  the 
nucleotid  may  be  illustrated  as  follows: 

OH 
\ 
H3P04  +  C6H904.C6H4N60     =     0  =  P  —  O.C6H803.C6H4N&0  +  H20 

OH7 


THE  PURIN  METABOLISM  431 

The  bindings  that  occur  to  form  polynucleotids  involve  the  phosphoric 
acid  groups,  of  which  yeast  nucleic  acid  may  serve  as  illustration. 

OH 

0  =  P— O.C6H803.C5H4N6 

o( 

O  -  P— O .  C5H803 .  C5H4N6O 

/  V? 

Q 

O  =  P— O .  C6H803 .  C4H4N3O 

/ 

o 

0  =  P— O  C6H803.C4H3N202 

oh7 

The.purins  contained  in  yeast  polynucleotid  are  guanin  and  adenin, 
the  pyrimidins  are  cytosin  and  uracil.  This  may  be  regarded  as  a 
representative  type,  since  the  nucleic  acid  of  the  wheat  embryo  and 
of  the  thymus  gland  seem  very  similar  if  not  identical  in  composition. 

The  pentose,  d-ribose,  one  of  the  eight  possible  pentoses,  is  scarcely 
known  in  nature  outside  of  the  plant  and  animal  nucleic  acids. 

The  pyrimidins  are  derivatives  of  the  pyrimidin  ring  or  nucleus, 
that  is  represented  as  follows,  with  numbers  to  indicate  the  bindings: 

1  N  =  CH  6 

2  HC       CH  5 

il        II 

3  N  —  CH  4 

The  three  pyrimidins  that  occur  in  nucleic  acids  are  thymin,  cytosin, 
and  uracil.    Thymin:    5  methyl-2-6-dioxy-pyrimidin 

HN  — CO 

OC       C.CH3 

HN  — CH 

Cytosin :     6-amino-2-oxy-pyrimidin 

N  =  C.NH2 

OC      CH 

I        II 
HN  — CH 

Uracil :     2-6-dioxy-pyrimidin 


HN  — CO 

OC       CH 

I         II 
HN  — CH 


432     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

The  purin  bases  are  derivatives  of  the  purin  ring  or  nucleus,  repre- 
sented as  follows  with  numbers  for  the  bindings: 

1  N  =  CH  6 

2  HC    5C-NH7 


II    II 

N  — C 


> 


XJH  8 

—  N 
4  9 


The  three  purin  bases  that  occur  in  nucleic  acids  are  adenin,  guanin, 

and  hypoxanthin. 

Adenin:    6-amino-purin,  C5H&N5. 

N  =  C.NH2 
HC      C  —  NH 


!  —  N 


Guanin:    2-amino-6-oxy-purin,  C5H5N50. 


HN  — CO 

L    A 


NH2.C       C  — NH 

,|    II      V* 

N 


—  C  — N 


Hypoxanthin:   6-oxy-purin,  C5H4N4O 

HN  — CO 

-NH 


Hi     A 


/CH 

N  — C  — N 

The  Nucleoproteins  in  Digestion. — The  pepsin  and  hydrochloric  acid 
of  the  gastric  juice  split  the  nucleoproteins  into  protein  and  nuclein, 
and  then  split  the  nuclein  into  protein  and  nucleic  acid.  These  are 
simple  reactions  of  hydrolytic  cleavage,  and  once  set  free  the  proteins 
join  the  other  proteins  of  the  diet. 

The  polynucleotids  are  entirely  resistant  to  the  action  of  pepsin- 
HC1  in  the  gastric  juice;  the  nucleic  acid  is  not  split  into  its  component 
mononucleotids.  This  means  that  the  gastric  secretion  contains  no 
nucleinase.  The  mononucleotids  are  also  resistant  to  hydrolysis  in 
the  stomach;  phosphoric  acid  is  not  split  off  from  combination  with 
nucleosids.  This  means  that  the  gastric  secretion  contains  no  nucleo- 
tidase. Nucleosids  are  resistant  to  the  action  of  pepsin-HCl,  and  are 
not  split  into  their  component  pentose  and  base.  This  means  that  the 
gastric  juice  contains  no  nucleosidase.    In  a  word?  the  gastric  juice  is 


THE  PURIN  METABOLISM  433 

without  effect  on  nucleic  acid,  nucleotids  and  nucleosids;  it  simply 
splits  the  protein  from  nucleoproteins  and  nucleins. 

The  pancreatic  juice  has  no  greater  activities  in  the  direction  of  these 
substances  than  has  pepsin.  Trypsin  will  split  off  the  protein  from 
nucleoprotein  and  from  nuclein.  It  cannot  split  the  nucleic  acid  into 
mononucleotids;  it  cannot  cleave  from  the  latter  the  phosphoric  acid 
and  set  free  the  nucleosids;  and  it  cannot  split  the  nucleosids  into  pentose 
and  base.  In  other  words,  the  pancreatic  secretion  is  devoid  of  nuclei- 
nase,  nucleotidase,  and  nucleosidase. 

The  succus  entericus,  however,  contains  active  ferments  for  these 
bodies.  Under  its  action  the  polynucleotids  are  split  into  their  com- 
ponent mononucleotids.  The  intestinal  juice,  therefore,  contains 
nucleinase.  Both  purin  and  pyrimidin  nucleotids  are  split  by  the 
intestinal  juice  into  phosphoric  acid  and  the  component  purin  and 
pyrimidin  nucleosids.  The  secretion,  therefore,  contains  nucleotidase. 
Here  the  action  stops.  The  nucleosids  are  not  split  into  their  com- 
ponent pentose  and  base.  The  juice  contains  no  nucleosidase.  The 
phosphoric  acid  combines  with  ever-present  alkali.  The  nucleosids  are 
resorbed  unchanged,  so  far  as  the  alimentary  juices  are  concerned. 

These  various  experiments  have  been  carried  out  in  glass  with  diges- 
tive juices  obtained  by  fistuhe.  When  the  experiments  are  carried 
out  in  the  dog,  with  appropriate  fistulas,  it  is  found  that  purin  bases 
are  set  free.  This  must  be  due  not  to  the  action  of  the  digestive  juices, 
but  to  bacteria.  By  direct  test  bacteria  can  be  shown  to  possess  nucleo- 
sidase. To  what  extent  this  bacterial  cleavage  occurs  in  the  normal 
alimentary  tract  is  unknown.  Purin  bases  are  normally  present  in 
the  stools.  Ribose  thus  set  free  would  become  liable  to  fermentation, 
as  the  intestinal  bacteria  can  ferment  pentose,  at  least  arabinose. 
Otherwise,  the  pentose  and  bases  would  be  available  for  resorption, 
as  it  is  not  likely  that  the  purins  or  pyrimidins  would  be  oxidized  in 
the  intestine. 

The  sum  total  of  our  information  may  be  incorporated  in  the  state- 
ment that  through  the  action  of  the  digestive  juices  nucleic  acids 
are  split  into  mononucleotids;  these  into  nucleosids;  and  these,  to  an 
indeterminate  extent,  are  split  by  bacteria  into  pentose  and  bases. 
Available  for  resorption,  therefore,  are  nucleosids,  pentose,  purin 
and  pyrimidin  bases.  How  complete  these  reactions  are  cannot  be 
stated.  It  seems  probable  that  unsplit  nucleic  acid  and  unsplit  nucleo- 
tids could  also  be  absorbed.  The  feces  contain  small  amounts  of  purin 
bases.  These  proceed  partly  from  the  purin  set  free  from  the  nucleic 
acid  of  the  diet  by  bacteria;  in  part,  however,  they  must  be  derived 
from  the  digestion  and  bacterial  cleavage  of  dead  bacteria  and  desqua- 
mated epithelial  cells. 

The  Fate  of  the  Resorbed  Nucleic  Acid,  Nucleotids,  Nucleosids,  Pentose, 

Purins,    and  Pyrimidins. — The  mucous  membrane,   the  membrane   of 

resorption,  presents  here  again  evidence  of  its  metabolic  functions. 

Extracts  of  the  mucous  membrane  exhibit,  as  does  the  intestinal  juice, 

28 


434      METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

the  power  of  splitting  nucleic  acid  into  the  component  mononucleotids 
and  transferring  these  into  nucleosids  by  splitting  off  the  phosphoric 
acid;  this  extract  also  is  able  to  split  the  nucleosid  into  the  component 
pentose,  purin  and  pyrimidin  bases.  Obviously  any  incompleteness 
in  the  digestion  of  the  nucleic  acids  and  nucleotids  by  the  succus 
entericus  may  be  made  good  during  the  process  of  resorption.  And  in 
addition,  the  nucleosids  will  be  split  into  their  component  bodies. 
How  complete  are  these  reactions,  cannot  be  stated.  It  is,  however, 
a  fair  assumption,  when  one  contemplates  the  other  digestive  functions 
of  the  intestinal  mucosa,  that  it  is  complete.  At  least  until  it  is  proved 
incomplete  we  may  fairly  assume  that  it  is  complete.  Therefore  the 
products  of  the  digestion  of  nucleic  acids  as  finally  present  in  the  blood 
of  the  portal  vein  are  phosphoric  acid  combined  with  bases,  ribose,  free 
purin  bases  and  free  pyrimidin  bases.  Under  ordinary  conditions  of 
diet  the  amount  of  nucleic  acids  ingested  is  not  large,  since  except 
in  especial  foods,  like  sweetbreads,  the  content  of  nucleic  acids  is  not 
heavy. 

THE   METABOLISM   OF   NUCLEIC    ACID 

This  is  to  the  pathologist  as  well  as  to  the  physiologist  one  of  the 
most  interesting  of  the  metabolisms.  Presenting  to  the  biologist  several 
of  the  most  striking  syntheses  in  the  body,  it  appeals  to  the  pathologist 
by  reason  of  the  relation  of  gout  to  the  purins.  The  study  of  gout 
brought  into  physiology  and  for  years  maintained  there  erroneous 
conceptions  of  the  nucleic  metabolism.  And  the  neglect  to  separate 
the  exogenous  from  the  endogenous  catabolism  of  nuclein  is  the  reef 
on  which  many  a  thesis  of  pathology  has  gone  to  wreck. 

The  nucleic  metabolism,  like  those  of  fat,  sugar  and  protein  is  to 
be  divided  into  anabolism  and  catabolism. 


THE    ANABOLISM   OF   NUCLEIC    ACID 

The  conjugation  of  the  nucleic  acid  with  proteins  to  form  nucleins 
and  nucleoproteins  is  comparable  to  the  anabolism  of  protein.  We 
are  here  concerned  only  with  the  synthesis  of  the  nucleic  acids.  Included 
herein  are  the  synthesis  of  the  ribose,  purin  and  pyrimidin  bases;  the 
combination  of  these  into  ribosids,  the  nucleosids;  the  joining  of  nucleo- 
sids with  phosphoric  acid  to  form  nucleotids;  and  the  union  of  mono- 
nucleotids to  form  polynucleotids.  The  native  nucleic  acids  do  not 
all  pass  through  these  stages.  As  previously  stated,  native  nucleic 
acid  may  be  either  mononucleotid  or  polynucleotid. 

The  anabolism  of  nucleic  acid  presents  the  most  striking  illustration 
of  autogenous  function.  The  anabolism  of  carbohydrate,  fat  and 
protein  within  the  body  are  really  little  more  than  reconstructions, 
for  the  materials  of  which  (in  the  sense  of  definite  chemical  substances) 


THE  ANABOLISM  OF  NUCLEIC  ACID  435 

the  animal  body  is  dependent  upon  the  diet.  But  in  the  case  of  nucleic 
acid  we  observe  autogeny.  The  body  is  entirely  independent  of  nucleic 
acid  or  any  one  of  its  components  in  the  diet;  it  synthesizes  its  pentose, 
purins  and  pyrimidins.  The  pentose  is  synthesized  from  hexose; 
the  purins  and  pyrimidins  are  derived  from  protein,  not  from  pre- 
existing purins  or  pyrimidins.  Not  only  can  the  body  effect  these 
syntheses,  but  it  is  most  probable  that  it  always  does  so;  preformed 
pentose,  purin  and  pyrimidin  of  the  diet  are  in  our  present  opinion 
not  utilized  in  the  formation  of  nucleic  acid,  for  which  the  body  relies 
entirely  upon  its  own  synthesized  components.  It  is  not  known  whether 
there  is  anything  specific,  in  the  biological  sense,  in  the  nucleic  acids. 
So  far  as  present  investigations  go,  no  signs  of  such  biological  specificity 
have  been  revealed.  The  nucleic  acids  are  not  colloidal;  they  are  acids, 
diffusible,  and  their  salts  are  subject  to  electrolytic  as  well  as  hydro- 
lytic  dissociation.  There  is  a  certain  isomerism  possible  in  the  purins. 
As  will  be  later  pointed  out,  there  are  two  known  isomers  of  uric  acid. 
It  is  possible  that  such  differences  might  extend  to  the  purin  bases, 
and  in  this  way  the  nucleic  acids  might  possess  chemical  individuality 
beyond  the  apparent  variations  in  composition. 

That  the  animal  organism  forms  nucleic  acid  independently  of  the 
input  of  any  of  its  components  preformed,  apart  from  phosphoric  acid, 
is  shown  in  many  ways.  The  eggs  of  birds  and  insects  contain  no  pen- 
tose, purin  or  pyrimidin;  the  larvse  and  chicks  contain  many  cells 
fully  endowed  with  nucleic  acid.  The  young  of  mammals  live  on  milk 
which  is  free  of  pentose,  purins  and  pyrimidins;  normal  cellular  growth 
and  reproduction  are,  of  course,  maintained.  The  case  has  been  reported 
of  a  young  man  who  grew  up  on  milk  as  his  sole  diet.  In  starvation  the 
nucleic  metabolism  pursues  the  even  tenor  of  its  way.  The  migrating 
salmon,  who  do  not  feed,  form  large  amounts  of  nucleic  acid  in  the 
ripening  milt.  There  is  no  doubt  of  the  absolute  capacity  of  the 
body  to  synthesize  to  the  fullest  extent  the  components  of  the  several 
nucleosids. 

The  origin  of  the  ribose  is  to  be  sought  in  the  glucose  of  the  body. 
How  this  is  accomplished  we  do  not  know;  but  that  it  is  accomplished 
from  glucose  seems  certain.  Under  certain  pathological  conditions 
arabinose  is  eliminated  in  the  urine.  This  may,  of  course,  have  been 
derived  from  the  ribose  of  the  nucleic  acid.  But  in  some  cases  of 
pentosuria,  amounts  of  arabinose  are  eliminated  so  large  as  to  seem 
entirely  outside  of  the  possibilities  of  the  known  nucleic  catabolism, 
as  estimated  by  the  purin  output.  Under  these  circumstances  the 
arabinose  must  have  been  derived  from  glucose.  That  the  body  forms 
glucose  from  pentose  is  certain;  and  that  it  forms  pentose  from  glucose 
we  must  also  believe. 

The  purins  and  pyrimidins  are  in  some  way  derived  from  protein, 
or  rather  from  amino-acids.  For  the  direct  derivation  of  purin  from 
amino-acids  we  have  no  scheme  or  illustration.  This  statement  holds 
true  for  the  pyrimidin  ring.    But  with  the  pyrimidin  ring  once  formed, 


436     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

we  may  conceive  of  the  formation  of  purin  by  the  union  of  pyrimidin 
ring  and  imidazol.  The  imidazol  exists  preformed  in  histidin,  an 
almost  invariable  component  of  proteins. 


CH— NH 

yen 

—  N 


H2 
CHNH2 


i 


OOH 

When  glucose  is  acted  upon  by  ammonium  zinc-hydroxid,  methyl- 
imidazol  is  formed. 

CH3 

C     —  NH 

II  XCH 

CH  — N 

From  this  reaction  the  direct  derivation  of  imidazol  from  fatty  acids 
under  the  action  of  alkali  is  not  difficult  of  conception  theoretically. 
But  in  any  event  the  imidazol  group  exists  in  the  body  preformed  in 
histidin.  The  formation  of  purin  from  the  pyrimidin  ring  plus  imidazol 
is  illustrated  as  follows: 

N  =  CH  N  =  CH 

|  HC-NH  |         || 

HC       CH      +         ||  \rTT  -*        HC        C  — NH 

JU&I  .A-     /  I!        ||         > 

N  — C  — N 

We  may  in  this  manner  get  a  general  idea  of  the  origin  of  the  purin 
bases;  but  of  the  origin  of  the  pyrimidins  we  know  nothing.  None  of 
the  methods  of  laboratory  synthesis  of  pyrimidin  throw  any  light 
upon  its  derivation  within  the  body. 

Once  formed,  the  purin  bases  are  combined  with  ribose  to  form  purin 
ribosids;  the  pyrimidin  bases  are  combined  with  ribose  to  form  pyrimidin 
ribosids.  The  ribosids  (nucleosids)  are  then  combined  with  phosphoric 
acid,  ever  present  in  the  diet,  to  form  the  corresponding  mononucleotids. 
These  may  be  combined  with  protein  to  form  nuclein  and  the  nuclein 
with  protein  to  form  simple  nucleic  acids.  Or  nucleotids  (four  in 
number  usually,  two  purin  and  two  pyrimidin  nucleotids)  are  combined 
to  form  a  polynucleotid,  which  combined  with  protein  forms  nuclein 
and  united  with  further  protein  forms  complex  nucleic  acid.  In  a 
certain  sense  we  may  compare  the  mononucleotid  and  the  polynucleotid 
with  peptone  and  albumin.    These  reactions  of  synthesis  we  hold  are 


THE  ANABOLISM  OF  NUCLEIC  ACID  437 

accomplished  within  the  cell  nucleus.  When  a  cell  divides,  there  must 
be  a  marked  velocity  of  this  synthesis  for  the  formation  of  chromatin 
for  the  two  nuclei;  and  in  the  rapid  cell  divisions  of  the  early  embryo, 
these  syntheses  are  the  most  striking  features.  We  have  spoken  of 
nucleic  acids  as  being  nuclear  constituents.  To  this  there  seems  to 
be  one  exception.  Muscle  contains  inosinic  acid  in  amounts  and  under 
circumstances  that  seem  to  preclude  its  being  an  intranuclear  con- 
stituent. We  are,  therefore,  forced  to  assume  that  in  the  case  of 
muscle,  the  nucleotid  (inosinic  acid)  is  in  some  way  combined  with  the 
protoplasm,  in  the  so-called  muscle  plasma. 

A  number  of  different  nucleotids  have  been  isolated  and  studied. 
Guanylic  acid  (the  nucleotid  of  guanosin,  which  is  the  ribosid  of  guanin) 
has  been  recovered  from  the  pancreas,  liver,  and  spleen.  Inosinic  acid 
(the  nucleotid  of  inosin,  which  is  the  ribosid  of  hypoxanthin)  is  present 
in  muscle.  The  corresponding  adenosinic  acid  has  not  been  isolated. 
Of  the  three  pyrimidin  nucleotids  only  one  has  been  isolated — cytidin, 
containing  cytosin.  It  is  assumed  that  they  all  exist  in  different  simple 
as  well  as  in  complex  nucleic  acids.  Of  polynucleotids  those  occurring 
in  the  milt  of  the  salmon  and  of  the  herring,  in  the  thymus,  in  yeast 
and  in  the  embryo  of  the  wheat  have  been  well  studied.  These  all 
contain  adenin  and  guanin  ribosids.  Concerning  the  pyrimidins  the 
facts  are  not  so  definite.  In  the  animal  polynucleotids,  thymin,  cytosin, 
and  uracil  are  recovered,  though  but  two  can  exist  preformed.  The 
uracil  is  easily  derived  from  cytosin,  and  may  have  been  formed  from 
it  in  the  manipulations  of  isolation.  In  the  triticonucleic  acid  of  wheat, 
however,  only  cytosin  and  uracil  are  found;  either  the  two  existed 
preformed  or  only  cytosin  (ribosid)  existed,  and  the  uracil  was  formed 
from  it  in  the  manipulations  of  isolation.  The  same  question  exists  for 
both  hypoxanthin  and  uracil.  They  can  be  formed  by  oxidation  from 
adenin  and  cytosin;  but  there  is  evidence  tending  to  indicate  that  they 
do  exist  preformed  in  nucleic  acids. 

When  purins,  pyrimidins  and  pentose  are  carried  to  the  cells  in  the 
blood  stream,  do  the  cells  use  these  exogenous  substances  and  of  them 
form  nucleic  acids,  thus  sparing  the  work  of  synthesis?  It  will  be 
recalled  that  the  products  of  the  digestion  of  nucleic  acid  were  nucleo- 
sids.  We  learned  further  that  these  nucleosids  were  split  in  the  wall 
of  the  intestine  during  resorption.  The  liver  contains  nucleosidase, 
so  that  if  any  escaped  cleavage  in  the  intestinal  wall,  they  would  be 
split  in  the  liver.  Therefore,  in  the  circulating  blood  would  be  found 
(in  the  absence  of  any  oxidation  or  deaminization),  ribose  and  the 
purin  and  pyrimidin  bases.  Now  the  liver  is  active  in  deaminization, 
and  it  will  need  to  be  shown  as  a  matter  of  fact  that  adenin,  guanin, 
and  cytosin  pass  undeaminizated  through  the  liver  into  the  blood  of  the 
vena  cava. 

Assuming  for  the  sake  of  argument  that  these  bases  could  pass  through 
the  liver  unchanged,  is  there  evidence  that  the  cells  use  them  in  the 
syntheses  of  nucleic  acid?    There  is  no  evidence  for  this  view;  there 


438     METABOLISM  OF  CREATIN-CREATIN1N  AND  OF  PURIN 

is  also  no  direct  evidence  against  it.  But  against  this  view  is  the  posi- 
tive fact  that  exogenous  purins  appear  quickly  in  the  urine.  The 
ingestion  of  a  sweetbread  is  quickly  followed  by  the  elimination  of  a 
large  amount  of  purin.  That  this  elimination  of  exogenous  purin  is 
complete  in  the  quantitative  sense  cannot  be  stated  because  we  have 
no  reliable  way  of  estimating  the  amount  of  purins  in  the  ingested 
sweetbread.  But  heavy  this  elimination  is  and  prompt.  The  endog- 
enous purins  of  the  urine  run  remarkably  even.  When  exogenous 
purins  are  ingested,  the  purin  output  rises  in  such  a  manner  as  to 
suggest  strongly  that  their  elimination  is  quantitative.  That  the 
body  cells  should  put  on  and  lay  off  the  syntheses  of  purins  in  such 
a  manner  as  predicated,  seems  to  the  writer  improbable,  and  it  will 
be  here  assumed  that  the  cells  of  the  body  always  synthesize  the  purins, 
pyrimidins  and  ribose  out  of  which  are  formed  in  the  same  cells  the 
nucleic  acids.  Just  as  in  the  case  of  the  protein  anabolism,  synthesis 
is  needed  for  wear-and-tear,  as  well  as  for  the  construction  of  young 
cells. 

Pathological  Variations. — We  have  no  data  whatever  tending  to  indi- 
cate that  under  conditions  of  disease  quantitative  or  qualitative  varia- 
tions exist  in  the  anabolism  of  nucleic  acid.  There  are  many  conditions 
in  which  excessive  cell  multiplication  occurs — in  leukocytosis,  leukemia, 
in  rapidly  growing  neoplasms — states  of  cell  multiplication  in  which 
the  excessive  growth  follows  some  abnormal  stimulation.  Of  the 
nature  of  the  abnormal  stimuli  we  have  neither  experimental  nor 
dynamic  conception.  In  the  nuclei  of  cells  formed  in  such  states  of 
abnormally  rapid  multiplication,  histological  appearances  indicate 
at  times  unusual  arrangements,  deficient  or  excessive  amounts  of  the 
chromatic  substance.  It  may,  however,  be  assumed  that  the  fault 
lies  not  in  the  function  of  anabolism  of  nucleic  acid,  but  rather  in  the 
utilization  of  the  nucleic  acid  after  its  synthesis.  The  defect  in  rachitis 
and  en  calcification  lies  not  in  absence  or  superabundance  of  lime, 
but  in  abnormal  utilization  of  the  lime.  And  in  like  manner  for  the 
present  at  least,  we  regard  the  aberrant  relations  of  the  chromatin  of 
abnormal  cells  to  lie  not  in  variations  in  the  anabolism  of  nucleic  acid, 
but  rather  in  the  utilization  of  nucleic  acid. 

THE   CATABOLISM   OF   NUCLEIC    ACID 

The  experimental  investigations  of  the  last  ten  years  have  disclosed 
a  most  interesting  and  instructive  series  of  enzymic  reactions  affecting 
the  nucleic  acids  and  their  components.  When  a  cell  dies  its  chromatic 
substance  undergoes  alterations  whose  microscopic  appearances  are 
best  interpreted  as  indicating  solution.  The  strands  lose  their  power 
of  specific  staining,  the  fibrillse  become  undifferentiated  and  revert, 
so  to  speak,  to  the  condition  of  undifferentiated  protoplasm.  This 
solution  the  biologist  regards  as  due  to  digestion.  The  reactions  that 
in  the  death  of  the  cell  involve  the  chromatin  in  toto,  may  be  regarded 


THE  CATABOLISM  OF  NUCLEIC  ACID  439 

as  involving  portions  of  it  in  the  wear-and-tear  of  cellular  life.  The 
first  reactions  are  hydrolytic  cleavages,  due  to  the  action  of  the  intra- 
cellular proteolytic  enzymes,  and  leading  to  the  splitting  off  of  the  two 
molecules  of  protein  and  the  setting  free  of  the  nucleic  acid.  This 
then  become  available  for  the  catabolic  reactions  of  the  nucleic  ferments. 

Nucleinase,  the  enzyme  that  accelerates  the  cleavage  of  polynucleo- 
tids  to  mononucleotids,  is  experimentally  present  in  all  organs  and 
tissues.  The  ferment  is  specific  in  the  sense  that  it  carries  the  reaction 
only  to  the  stage  of  mononucleotid.  It  is  not  specific  in  this  sense: 
the  ferment  of  an  animal  body  will  split  the  polynucleotids  of  different 
plants. 

Nucleotidase,  the  ferment  that  accelerates  the  cleavage  of  the  mono- 
nucleotids to  nucleosids,  is  also  experimentally  present  in  all  organs 
and  tissues.  It  is  specific  in  the  same  sense  as  nucleinase  is  specific — 
its  activities  are  limited  to  the  single  reaction. 

Nucleosidase,  the  enzyme  that  accelerates  the  cleavage  of  the  nucleo- 
sids, the  ribosids,  into  the  component  ribose  and  purin  or  pyrimidin, 
is  likewise  experimentally  present  in  all  tissues  and  organs.  It  is  specific 
in  the  sense  that  it  will  not  split  other  glucosids,  though  it  does  cleave 
the  ribosids  of  purin  and  pyrimidin. 

These  three  hydrolytic  ferments,  operating  side  by  side  in  the  tissues, 
furnish  striking  illustrations  of  enzyme  action  that  is  purely  quantita- 
tive but  nevertheless  strictly  limited  to  a  particular  substrate  class. 
Nucleic  acid  is  hydrolyzed  very  slowly  in  sterile  water  at  ordinary  tem- 
perature, and  these  enzymes  are  pure  accelerators.  But  the  field  or 
scope  of  their  accelerating  influence  is  confined  to  one  class  of  substrate. 

These  reactions  occur  exclusively,  it  is  now  held,  within  cells.  The 
result  is  the  setting  free  of  purin  bases,  pyrimidin  bases  and  ribose. 
The  fate  of  the  latter,  except  as  expressed  in  the  assumption  that  it  is 
somewhere  and  somehow  converted  into  d-glucose,  is  unknown.  Before 
we  discuss  the  enzymic  catabolism  of  the  bases,  it  will  be  best  to  state 
the  perfectly  demonstrated  qualitative  reactions  through  which  these 
substances  must  pass. 

Deaminization  and  oxidation  are  the  two  reactions  through  which 
the  purin  and  pyrimidin  bases  are  carried  to  the  end  products  of  their 
catabolism.    These  reactions  run  as  follows: 

Adenin  (6-amino-purin)  Hypoxanthin  (6-oxy-purin) 

N  =  C.NH2  HN  — CO 

HC       C  — NH  HC       C  — NH 

^>CH  +  H20        =  ^CH  +  O  = 

N  —  C  —  N  N  —  C  —  N 

Hypoxanthin  (6-oxy-purin)  Xanthin  (2-6-dioxy-purin) 

HN  —  CO  HN  —  CO 

HC       C  — NH  OC        C  — NH 

II     II     >CH  +  0    -  J,    I    J 

N  —  C  —  N  HN  —  C  —  N 


440     METABOLISM  OF  CREAT1N-CREATININ  AND  OF  PURIN 

Guanin  (2-amino-6-oxy-purin)  Xanthin  (2-6-dioxy-purin) 

HN  —  CO  HN  —  CO 

NH2.C  C  — NH  OC         C  —  NH 

>CH  +  H20      =  jl         ^>CH  +  O  = 

HN  —  C  —  N 


C  — N 


Xanthin  (2-6-dioxy-purin)  Uric  acid  (2-6-8-trioxy-purin) 

HN  —  CO  HN  —  CO 

OC   C  — NH  OC   C  —  NH 

>CH  +  O  -  >CO 

HN  —  C  —  N  HN  —  C  —  NH 


Cystosin  (6-amino-2-oxy-pyrimidin)        Uracil  (2-G-dioxy-pyrimidin) 

N  =  C.NH2  HN  — CO 

OC       CH        +     H20     m  OC      CH 

HN  — CH  HN  — CH 

Thymin  contains  a  methyl  group,  and  it  is  not  known  whether  the  body 
can  split  off  this  methyl  group.  Otherwise,  thymin  has  the  same  struc- 
ture as  uracil,  and  if  the  body  can  split  off  the  methyl  group,  uracil 
would  be  formed.  The  present  idea  is  that  monomethylpurins  and 
pyrimidins  are  not  in  the  body  convertible  into  oxypurins  and  oxy- 
pyrimidins. 

Thymin  (5-methyl-2-6-dioxy-pyrimidin)         Uracil  (2-6-dioxy-pyrimidin) 

HN  —  CO  HN  —  CO 

OC      C.CH3  -*  OC       CH 

I        II  I        II 

HN  —  CH  HN  —  CH 

The  urine  contains  a  trace  of  another  purin  base,  epiguanin,  which  is 
guanin  with  a  methyl  group  at  7.  It  has  never  been  isolated  from  a 
nucleic  acid.  Yet  the  analogy  with  the  methylpyrimidin  suggests  that 
it  occurs  in  some  particular  nucleic  acid  and  is  eliminated  unchanged. 
As  the  result  of  the  deaminization  of  the  amino-purins  and  cystosin, 
ammonia  is  set  free,  to  join  that  formed  in  the  deaminizations  of  the 
amino-acids. 

When  we  attempt  to  fix  the  conditions  of  occurrence  of  these  reactions 
of  deaminization  and  oxidation,  we  meet  with  contradictions  in  the 
published  data.  Since  these  substances  occur  in  all  cells  and  since  the 
nucleinases,  nucleotidases  and  nucleosidases  occur  in  all  cells,  it  might 
seem  to  follow  that  the  deaminization  and  oxidation  ferments  would 
also  occur  in  all  cells.  This  does  not  appear  to  be  the  case.  Just  as 
arginase  is  not  found  in  the  pancreas  but  is  found  in  the  liver,  so 
some  tissues  seem  to  be  devoid  of  the  oxidase.  The  experimental  diffi- 
culties are  marked,  and  in  work  of  this  kind  a  positive  result  proves 


THE  CATABOLISM  OF  NUCLEIC  ACID  441 

more  than  a  negative  result  disproves.  The  deaminization  ferment 
seems  to  be  the  more  widespread,  the  oxidation  ferment  the  more 
restricted.  In  different  animals  the  oxidation  ferment  has  been  found 
in  the  liver,  spleen,  kidneys,  lungs  and  in  the  intestinal  mucosa,  also 
in  muscle.  But  the  results  in  animals  of  different  species  are  not  uni- 
form. For  the  purpose  of  this  treatise  the  question  is  not  of  great 
importance.  Whether  all  organs  accomplish  these  reactions  or  whether 
the  purins  and  pyrimidins  have  to  be  transported  to  certain  organs 
by  the  circulation,  there  to  undergo  the  reactions,  may  for  the  present 
remain  undecided.  That  the  liver  is  especially  active  in  the  deaminiza- 
tion and  oxidation  of  the  exogenous  purins  is  known.  It  seems  possible 
also  that  the  reaction  of  deaminization  of  amino-purin  may  occur  while 
it  is  still  in  the  ribosid,  in  combination  with  the  pentose. 

The  ferments  for  the  deaminization  of  adenin  and  guanin  are  com- 
monly regarded  as  identical.  Nevertheless,  they  display  variations  that 
have  led  competent  investigators  to  regard  them  as  different  and  to  name 
them  respectively  guanase  and  adenase.  The  dualism  of  these  ferments 
is  supported  by  the  occurrence  of  the  guanin  gout  of  swine.  It  is 
possible  in  laboratory  experiments  to  have  the  reaction  of  deaminization 
precede  the  cleavage  of  the  ribosid.  Of  the  ferments  for  the  deamini- 
zation of  the  cytosin  little  is  known. 

The  reactions  are  never  complete,  i.  e.,  purin  and  pyrimidin  bases 
exist  with  uric  acid  in  all  normal  urines.  This  fact  is  probably  to  be 
regarded  as  an  incident  of  secretion  rather  than  one  of  reaction.  By 
that  we  mean  that  the  ratio  of  purin  bases  to  uric  acid  in  the  urine 
cannot  be  taken  as  indicating  the  relation  of  reaction.  Uric  acid,  purin, 
and  pyrimidin  bases  are  in  the  circulating  blood  that  passes  through 
the  kidney.  Naturally  the  kidney  eliminates.  It  is,  of  course,  possible 
that  the  kidney  normally  sweeps  them  all  out  quantitatively,  and  in 
that  event  the  ratio  found  in  the  urine  might  represent  the  relation  of 
reaction.  The  ratio  of  purin  bases  to  uric  acid  is  not  constant,  it  varies 
in  different  individuals  and  with  different  diets,  independent  of  the 
exogenous  purin.  The  question  is  one  of  importance  in  the  study  of 
gout,  but  there  seems  to  be  no  way  of  reaching  an  experimental  deter- 
mination of  the  exact  facts  and  relations. 

Are  the  products  of  the  catabolism  of  nucleic  acid  utilized  again 
in  the  body  for  the  synthesis  of  new  nucleic  acid?  Our  present  data 
speak  against  such  an  assumption.  It  is  our  understanding  that  when 
a  subject  is  on  a  purin-free  diet,  the  purin  output  of  the  body  repre- 
sents the  catabolism  of  nucleic  acid.  This  same  conclusion  was  drawn 
for  the  exogenous  purins.  This  is  not  strictly  true  in  one  sense,  because 
uric  acid  is  convertible  into  urea.  But  disregarding  this  fraction,  we 
believe  that  in  the  purin  output  is  represented  the  sum  total  of  the 
products  of  the  catabolism  of  nucleic  acid.  Since  the  purin  and  py- 
rimidin bases  are  identical,  whether  derived  from  the  catabolism  of 
nucleic  acids  of  the  diet  or  in  the  cells  of  the  body,  any  assumption 
that  the  body  could  utilize  the  exogenous  purins  of  the  diet  is  tanta- 


442     METABOLISM  OP  CREATIN-CREATIN1N.  AND  OF  PURIN 

mount  to  conceding  a  reutilization  of  the  products  of  catabolism  of 
the  endogenous  nucleic  acids.  Now  the  constancy  and  individuality 
of  the  purin  catabolism  and  the  lack  of  toleration  of  exogenous  purin 
on  the  part  of  the  body  speak  most  strongly  against  the  assumption 
of  any  utilization  of  preformed  purin  and  pyrimidin  bases  in  the 
anabolism  of  nucleic  acid.  The  anabolism  of  nucleic  acid  we  regard  as 
always  a  synthesis  de  novo,  from  the  amino-acids  of  protein  or  from 
amino-acids  and  sugar. 

Constancy  of  Catabolism  of  Nucleic  Acid. — Like  the  creatinin  metab- 
olism, the  catabolism  of  nucleic  acid  is  strikingly  constant  for  each 
individual.  Apparently  each  kilo  of  cellular  substance  produces  so 
much  purin,  pyrimidin  and  phosphoric  acid  per  day.  This  ratio  of 
nucleic  catabolism  to  cell  content  of  the  body  is  different  in  different 
individuals,  varies  with  age,  perhaps  with  sex,  and  to  some  extent  with 
occupation.  It  cannot  be  well  related  to  gross  body  weight  on  account 
of  the  differences  in  weight  of  skeleton  and  fat.  But  with  an  individual 
in  normal  weight,  it  is  striking  how  constant  the  purin  output  is  with 
a  regulated  life  and  with  the  exclusion  of  exogenous  purin  from  the 
diet.  Whatever  may  be  the  fraction  of  conversion  of  uric  acid  into 
urea  in  man,  it  seems  to  be  quite  unvarying  though  undetermined. 
The  output  of  purin  (we  select  purin  because  it  is  chemically  the  more 
controllable)  may  be  interpreted  in  a  direct  sense  to  represent  the 
pace  of  the  nucleic  metabolism  of  the  individual.  If  from  the  diet  of 
a  subject  we  exclude  purins,  creatin-creatinin  and  exogenous  protein, 
the  outputs  of  urea,  purin  and  creatinin  (apart  from  the  fractions  of 
uric  acid  and  creatinin  that  are  converted  into  urea)  are  independent 
entities  and  stand  for  specific  functions  of  the  body.  That  there  are 
correlations  between  these  three  functions  is  not  to  be  denied.  But  it  is 
correct  to  regard  them  as  specific  functions;  the  output  of  endogenous 
urea  (plus  ammonia)  representing  the  catabolism  of  protoplasm,  the 
output  of  creatinin  representing  the  catabolism  of  muscle  plasma,  and 
the  output  of  purin  representing  the  catabolism  of  nucleic  acid. 

While  it  is  true  that  the  purin  metabolism,  exogenous  purin  excluded, 
is  to  be  regarded  as  independent  of  the  protein  metabolism,  it  is  never- 
theless true  that  with  a  low  protein  input  that  curtails  greatly  the  ex- 
ogenous protein  catabolism,  the  purin  output  tends  to  fall  somewhat. 
It  is  possible  to  explain  this  without  any  abridgement  of  the  idea  of 
independence  of  the  two  metabolisms.  It  is  possible  that  within  certain 
limits  the  purin  catabolism  runs  parallel  to  the  work  of  the  cells;  and 
since  with  greatly  lowered  exogenous  protein  catabolism  the  work  of 
the  cells  of  the  liver  and  kidneys  is  reduced,  this  might  spare  nucleic 
wear-and-tear.  Secondly,  it  may  be  due  to  exaggeration  of  the  reaction 
of  uricolysis;  since  the  urea  concentration  in  the  liver  must  be  low,  in 
accordance  with  the  law  of  mass  action  the  conversion  of  uric  acid  into 
urea  would  be  increased. 

If  we  interpret  the  purin  output  to  represent  the  pace  of  the  nucleic 
catabolism,  it  is  clear  that  this  must  be  divided  among  the  different 


THE  CATABOLISM  OF  NUCLEIC  ACID  443 

cells  and  tissues  of  the  body  in  proportion  to  their  structure  and  func- 
tions. The  glandular  cells  richest  in  chromatin  are  to  be  regarded  as 
the  cells  most  active  in  nucleic  metabolism.  In  these  we  include  the 
liver,  the  lymphatic  organs  (spleen,  lymph  glands,  bone  marrow,  and 
the  circulating  leukocytes)  the  central  nervous  system,  the  kidneys, 
and  the  pancreas.  Muscle  plasma  contains,  however,  nucleic  acid 
combined  in  a  special  way  outside  the  nuclei,  of  which  more  later; 
the  nuclear  catabolism  of  nucleic  acid  in  muscle  cannot  be  large.  In 
a  general  sense,  therefore,  those  cells  are  most  active  producers  of 
purin  that  contain  the  largest  relation  of  mass  of  nuclei  to  mass  of  cell ; 
in  other  words,  the  largest  amount  of  nucleic  acid  in  relation  to  weight. 
This  is,  of  course,  just  what  would  be  expected  from  the  law  of  mass 
action.  But  there  is  evidently  another  factor.  Two  cells  with  equal 
relation  of  mass  of  nucleic  acid  to  total  mass  may  not  have  the  same 
intensity  of  metabolism;  the  span  of  life  may  be  longer  for  one  type 
of  cell,  the  wear-and-tear  less.  For  example,  it  seems  clear  that  the 
pace  of  life  is  faster  and  the  duration  of  life  shorter  in  a  circulating 
leukocyte  than  in  a  liver  or  kidney  cell.  At  least,  the  purin  output 
in  conditions  of  leukocytosis  and  in  leukemia  suggest  this  most  strongly. 
The  purin  output  of  leukemia  of  the  polymorphonuclear  type  is  much 
greater  than  in  apparently  equally  intense  leukemia  of  the  lymphocytic 
type.  The  particular  activity  of  the  nucleic  catabolism  in  the  leukocyte 
once  led  to  the  erroneous  assumption  that  these  cells  were  practically 
the  single  source  of  urinary  purins.  This  is,  of  course,  untrue;  but  the 
lymphatic  system  is  perhaps  the  most  prominent  single  tissue  with 
respect  to  the  catabolism  of  nucleic  acid. 

Extranuclear  Derivation  of  Purin. — That  purin  bases  are  not  derived  in 
the  body  outside  of  nucleic  acid  is  accepted  as  settled.  But  that  nucleic 
acid  exists  in  the  body  outside  of  nuclei  seems  to  be  equally  certain. 
Muscle  contains  apparently  a  nucleotid  termed  inosinic  acid,  combined 
with  the  muscle  plasma  in  some  way.  On  cleavage  this  mononucleic 
acid  yields  phosphoric  acid  and  a  ribosid  of  hypoxanthin.  On  cleavage 
of  the  nucleosid,  hypoxanthin  and  ribose  are  set  free.  Perfusion  of  the 
muscle  of  the  dog  yields  uric  acid  in  amounts  in  excess  of  the  apparent 
nuclear  content  of  that  tissue.  When  the  isolated  perfused  muscle 
is  tetanized,  the  elimination  of  uric  acid  is  much  increased  and  hypo- 
xanthin appears.  The  source  of  this  hypoxanthin  and  uric  acid  is 
obviously  to  be  sought  in  part  in  the  inosinic  acid;  in  part,  of  course, 
in  the  catabolism  of  the  nuclei  of  the  muscle  cells.  But  the  increase 
with  contractions  may  be  reasonably  attributed  in  large  part  to  the 
inosinic  acid.  It  is  possible,  in  some  individuals  at  least,  to  perform 
this  experiment  in  man.  It  is  well  known  that  muscular  work  does 
not  affect  the  twenty-four-hour  output  of  purins  in  man.  If,  however, 
heavy  muscular  work  be  done  and  the  urine  examined  for  purins  in 
short  periods,  it  will  be  found  that  there  is  a  wave  of  purin  output 
just  after  the  period  of  exercise,  to  be  followed  later  by  low  elimina- 
tion.   The  ratio  of  purin  bases  to  uric  acid  rises  during  the  period  of 


444     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

exercise;  later  the  ratio  returns  to  normal.  Apparently  the  exercise  of 
the  muscles  brings  out  rapidly  what  would  otherwise  have  been  brought 
out  slowly,  in  even  distribution.  From  these  observations  we  may  draw 
the  conclusion  that  there  is  a  regular  inosinic  catabolism  in  the  plasma 
of  muscle.  Heavy  exercise  does  not  affect  the  total  transformation  of  this 
fraction;  but  it  does  alter  the  distribution  in  time  and  also  so  exagger- 
ates it  during  the  period  or  actual  exercise  as  to  send  out  the  purin  bases 
before  they  can  be  oxidized  to  the  extent  normally  observed.  There- 
fore, with  heavy  work  the  urine  will  contain  a  little  more  purin  base 
and  a  little  less  uric  acid;  and  the  elimination  will  occur  in  a  wave 
rather  than  in  a  straight  line.  Just  how  large  is  the  fraction  of  this 
inosinic  acid  catabolism  as  compared  to  the  total  we  do  not  know;  it 
is  apparently  not  large.  The  experiment  has  been  reported  in  which 
as  the  result  of  forced  and  excessive  muscular  exercises,  the  urine  became 
for  a  time  practically  purin-free.  Although  there  is  no  obvious  chemical 
point  of  contact,  one  cannot  resist  the  thought  that  there  may  be  some 
connection  between  the  inosinic  and  the  creatin  catabolism  in  muscle 
plasma. 

The  Extranucleic  Origin  of  Uric  Acid. — In  all  the  above  discussion 
the  derivation  of  uric  acid  has  been  confined  to  preexisting  xanthin, 
this  derived  from  hypoxanthin,  guanin  and  adenin.  When  guanin 
(adenin  is  too  toxic  for  large  injections)  is  injected  into  animals,  it 
appears  in  the  urine  as  xanthin  and  uric  acid.  In  the  laboratory  it 
is  possible  to  reach  the  stage  of  uric  acid  from  adenin  and  guanin  in 
other  ways  than  by  the  steps  illustrated  in  the  scheme  on  pp.  439  and 
440.  But  this  fact  has  no  bearing  on  the  question  under  discussion.  Is 
uric  acid  derived  in  the  body  from  any  source  outside  of  the  purin 
bases?  Before  the  relations  of  the  purins  were  worked  out,  uric  acid 
was  supposed  to .  be  derived  from  several  sources.  Information  may 
be  sought  in  two  ways:  through  laboratory  synthesis;  and  by  observa- 
tion of  the  uric  acid  metabolism  of  lower  animals. 

Uric  acid  may  be  synthesized  by  heating  urea  with  either  glycocoll 
or  trichlorlactic  acid,  but  these  reactions  offer  no  information  of  use. 
Years  ago  it  was  believed  that  uric  acid  was  derived  from  common 
protein,  and  that  excess  of  protein  in  the  diet  (what  we  now  call  the 
exogenous  protein  fraction)  led  to  increase  in  the  uric  acid  in  the  urine. 
This  conception  is  totally  false.  Protein  has  no  influence  on  the  for- 
mation of  purins  except  through  the  nuclein  and  nucleic  acids  it  may 
carry.  Beyond  this,  the  purin  and  protein  metabolisms  are  independent 
of  each  other.  A  supposed  illustration  of  the  influence  of  protein  on 
the  purin  elimination  has  been  advanced  in  the  fact  that  the  purin 
output  is  lower  in  starvation  than  on  a  normal  diet  free  of  purin. 
The  interpretation  of  the  fact  is  faulty.  The  urea  output  is  also  less 
on  a  protein-starvation  diet  than  on  a  protein  diet  just  competent 
to  maintain  nitrogenous  balance.  Apparently,  when  put  to  it,  the 
metabolisms  cut  down  their  transformations,  an  expression  of  increase 
efficiency  of  operation  under  conditions  of  stress,  the  factor  of  wear 


THE  CATABOLISM  OF  NUCLEIC  ACID  445 

and  tear  is  lessened.     During  starvation,  furthermore,  the  secretions 
of  the  alimentary  tract  are  reduced.     (Cf.  also  page  442.) 

In  birds  and  in  some  reptiles,  uric  acid  is  the  chief  state  of  output 
of  nitrogen.  The  amino-acids  and  ammonia  derived  from  the  common 
catabolism  of  protein  are  in  the  bird  converted  into  uric  acid.  Ammo- 
nium salts,  urea  and  amino-acids  when  administered  to  birds  are 
eliminated  as  uric  acid.  Perfusion  of  the  liver  of  the  goose  with  these 
substances  leads  to  the  synthesis  there  of  uric  acid.  When  the  liver 
of  the  goose  is  extirpated,  the  uric  acid  output  falls  and  the  ammonia 
output  rises  proportionately.  When  lactic  acid  and  ammonia  are 
passed  through  the  isolated  liver  of  the  goose  or  mixed  with  the  liver 
pulp,  uric  acid  is  formed.  The  formation  of  uric  acid  in  the  bird  appears 
to  follow  the  following  course:  lactic  acid  is  first  converted  into  tar- 
tronic  acid  by  oxidation,  the  lactic  acid  being  derived  from  amino- 
acids  and  from  glucose;  tartronic  acid  then  adds  urea  to  form  dialuric 
acid,  which  finally  adds  another  molecule  of  urea  to  form  uric  acid. 

Lactic  acid  Tartronic  acid  Dialuric  acid 

CH3  COOH      NH2        NH  — CO 

I  I         /  /  J 

CHOH    -+        CHOH  +  C  =  O  =  CO       CHOH  +  2  H20 

I  I         \  \      I 

COOH        COOH      NH2        NH  —  CO 

Dialuric  acid  Uric  acid 

NH  —  CO  NH2  HN  —  CO 

CO  CHOH  +C=0         =       OC        C  —  NH 

\h-Ao  \h2  >CO+2H20 

HN  —  C  —  NH 

When  now  this  scheme  is  applied  to  the  mammals,  it  fails.  When 
lactic  acid  or  tartronic  acid  is  fed  to  mammals  with  urea,  no  uric 
acid  is  formed  even  when  pyrimidin  is  added.  When  perfusion  of 
the  liver  or  experiments  with  liver  pulp  are  done  with  tartronic  acid 
and  urea,  no  uric  acid  is  formed  therefrom.  Even  when  dialuric  acid 
is  used,  the  results  are  negative,  as  they  are  also  with  the  amids  of  tar- 
tronic acid.  The  above  scheme,  while  it  holds  for  birds,  has  no  appli- 
cation to  the  purin  metabolism  of  man. 

Xo  other  plausible  scheme  for  the  direct  synthesis  of  uric  acid  has 
been  suggested.  The  data  on  the  derivation  of  uric  acid  from  the  purin 
bases  meets  every  requirement;  and  we,  therefore,  rest  all  discussion 
of  the  role  of  uric  acid  in  physiology  and  pathology  upon  the  single 
origination  of  uric  acid  from  purin  bases;  and  antecedent  to  this  the 
single  derivation  of  the  purin  bases  from  nucleic  and  inosinic  acids. 

The  endogenous  purins  vary  in  normal  individuals  from  0.15  to 
0.40  gram  per  day,  the  variations  being  from  individual  to  individual; 
in  the  same  subject  the  output  is  very  constant  from  day  to  day.  Milk 
or  egg  diet  is  the  only  known  purin-free  diet.    Of  this  output,  the  larger 


446     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

part  is  in  the  state  of  uric  acid;  of  purin  bases  the  output  may  be  from 
10  to  40  milligrams  per  day.  Usually  xanthin  and  hypoxanthin  make 
up  the  larger  part  of  the  purin  bases;  adenin  and  guanin  are  some- 
times present,  but  only  in  traces,  and  guanin  in  particular  is  rarely 
eliminated.  The  purin  output  in  infancy  is  high  in  relation  to  the 
weight  of  tissue — an  expression  of  intense  nuclear  metabolism.  On  a 
purin-free  diet  the  curve  of  purin  output  presents  the  highest  point 
during  the  morning,  the  lowest  at  night. 

The  Exogenous  Purin. — The  normal  urine  of  subjects  on  mixed  diets 
contains  more  purin  of  exogenous  than  of  endogenous  derivation. 
The  exogenous  purins  are  derived  from  four  groups  of  ingredients  in 
the  diet. 

The  glands  of  the  animal  body  are  quite  rich  in  purin.  The  thymus, 
which  is  the  sweetbread  of  the  table,  is  very  rich  in  purin,  containing 
to  the  100  gram  of  fresh  gland  nearly  a  gram  and  a  half  of  purin. 
Pancreas,  which  is  often  served  as  sweetbread,  contains  about  a  half 
gram  of  purin  to  the  100  grams  of  fresh  gland.  Kidney  and  liver  are 
about  as  rich  as  pancreas;  if  different,  perhaps  less.  Brain  is  fairly 
rich. 

The  flesh  of  animals,  more  commonly  used  for  food  than  the  internal 
glands,  is  not  rich  in  purins.  In  the  muscle  are  two  fractions;  that 
derived  from  the  nuclei  and  that  originating  in  the  inosinic  acid.  The 
input  due  to  the  inosinic  acid  can  scarcely  be  more  than  0.05  gram 
per  day.  The  flesh  of  fowl  is  richer  in  purin  than  the  flesh  of  adult 
beef  and  mutton;  veal  and  lamb  are  somewhat  richer.  As  mixed  diets 
go,  probably  some  200  milligrams  of  purin  are  derived  daily  in  this 
fraction  of  the  exogenous  purin. 

Vegetables  are  commonly  supposed  to  be  poor  in  purins,  and  this 
is  true  of  many.  The  legumens,  however,  are  quite  rich  in  purins, 
as  may  be  observed  in  analyses  of  the  urine  of  subjects  on  a  liberal 
input  of  peas  or  beans.  The  root  vegetables  are  almost  purin-free. 
The  grains  contain  small  amounts,  so  that  bread  contains  about  100 
milligrams  to  the  kilo. 

The  common  beverages  contain  purins.  Malted  liquors  contain 
more  than  traces.  Coffee,  tea  and  cocoa  are  rich  in  purins,  since  the 
alkaloids  of  these  plants  are  methylpurins.  CafTein  is  1-3-7-trimethyl- 
purin,  theophyllin  is  1-3-dimethylpurin,  theobromin  is  3-7-dimethyl- 
purin.  In  addition  to  these  methylpurins,  the  extracts  of  tea  and 
coffee  contain  amino-  and  oxy purins,  tea  being  rich  in  adenin. 

In  the  catabolism  of  the  exogenous  purins,  it  is  quite  certain  that 
for  ordinary  inputs  the  amino-  and  oxy-purins  are  eliminated  in  large 
part  as  uric  acid,  having  been  deaminizated  and  oxidized  in  the  liver. 
There  may  be  a  slight  increase  in  the  purin  bases,  but  by  far  the  larger 
part  is  eliminated  as  uric  acid.  For  the  methylpurins,  on  the  other 
hand,  it  is  fairly  certain  that  they  are  not  oxidizable  to  uric  acid;  the 
body  is  able  to  burn  one  or  two  but  not  the  last  methyl  group,  thus 
eliminating  them  as  a  monomethylpurin.     From  the  urine  of  persons 


THE  CATABOLISM  OF  NUCLEIC  ACID  447 

accustomed  to  the  use  of  tea  and  coffee,  four  different  methylpurins 
have  been  isolated — 1-methylpurin,  3-methylpurin,  7-methylpurin, 
and  1-7-dimethylpurin.  These  are  the  end  products  of  the  catabolism 
of  the  methylpurins  of  the  beverages  named.  It  is  the  present  view- 
that  methylpurins  are  always  eliminated  as  methylpurins.  But  it 
must  not  be  forgotten  that  these  beverages  contain  in  addition  to 
methylpurins  also  amino-  and  oxy-purins.  A  dose  of  caffein  would 
be  eliminated  in  the  purin-base  fraction  of  the  urine;  but  following  the 
ingestion  of  a  cup  of  tea  or  coffee,  the  uric  acid  would  also  be  increased. 
The  content  of  amino-  and  oxy-purins  of  tea  and  coffee,  like  the  content 
of  methylpurins,  varies  in  different  samples;  and  since  the  strength 
of  the  beverages  varies  widely,  the  influence  of  the  consumption  of 
tea  and  coffee  upon  the  purins  and  the  uric  acid  of  the  urine  must  be 
varied.  In  the  urine  of  individuals  accustomed  to  the  regular  use  of 
tea  and  coffee,  the  methylpurin  bases  exceed  the  natural  purin  bases 
in  amount. 

There  is  also  a  difference  in  the  deaminization  and  oxidation  of 
isolated  purins  and  of  purins  in  the  natural  state.  If  adenin  and  guanin 
be  ingested,  it  will  be  found  that  a  large  fraction  will  reappear  in  the 
urine;  hypoxanthin  is  usually  oxidized  in  large  part  to  uric  acid.  But 
if  a  sweetbread  be  eaten  whose  adenin  and  guanin  content  is  equal 
to  the  amount  administered  in  the  experiment  stated,  there  will  be 
little  increase  in  the  purin  bases  of  the  urine;  the  increase  will  be  found 
largely  in  uric  acid.  The  explanation  of  this  fact  is  perhaps  to  be  found 
in  the  observation  that  in  some  tissues  the  nucleosid  is  deaminizated 
before  it  is  split  into  the  component  purin  and  pentose.  It  is  possible 
that  this  is  the  usual  order  of  reaction  in  the  intestinal  mucosa  and 
that  the  deaminization  there  may  be  confined  to  the  cleavage  of  the 
amino  group  from  the  nucleosid.  Another  explanation  would  lie  in 
the  mass  relations  of  resorption.  In  the  case  of  the  ingestion  of  the 
sweetbread,  the  process  of  digestion  is  slow  and  resorption  spread  out 
over  several  hours.  In  the  case  of  the  ingestion  of  a  dose  of  adenin 
or  guanin,  the  whole  mass  is  resorbed  in  a  short  time  and  it  might 
be  conceived  that  the  liver  could  not  accomplish  a  total  transformation 
and  bases  would  pass  in  part  into  the  blood  unchanged,  to  be  carried 
to  the  kidneys  and  eliminated.  From  this  point  of  view,  the  difference 
would  be  not  qualitative  but  quantitative. 

The  feces  contain  more  purin  bases  than  does  the  urine.  They  are 
derived  in  part  from  the  ingested  nucleic  acid,  in  part  from  the  cleavage 
by  bacteria  of  the  nucleic  acid  of  the  nuclei  of  the  desquamated  epi- 
thelial cells  and  of  bacteria  themselves. 

Under  varying  circumstances  affecting  the  exogenous  purins,  the 
total  urinary  output  of  purins  may  vary  from  less  than  a  half  gram 
to  2  grams  per  day.    As  a  rule  a  gram  is  not  exceeded. 

The  Oxidation  of  Uric  Acid. — The  uric  acid  formed  in  the  body  is  not 
eliminated  quantitatively;  some  is  oxidized  to  urea.  The  magnitude 
of  this  fraction  is  difficult  if  not  impossible  of  definition  and  constitutes 


448     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

in  some  respects  the  crux  of  the  interpretation  of  the  purin  output. 
When  the  exogenous  purins  are  excluded  from  the  diet,  the  relations 
would  be  susceptible  of  direct  interpretation,  certainly  in  the  presence 
of  blood  analyses,  if  there  were  a  balance  between  production  and 
elimination.  But  since  it  is  certain  that  a  fraction  of  the  uric  acid 
is  oxidized,  unless  this  fraction  may  be  estimated,  the  foundation 
of  induction  fails.  In  many  ways  and  by  many  men  attempts  have 
been  made  to  measure  this  uricolysis.  If  one  administers  amounts 
of  uric  acid  up  to  a  gram,  from  One-fourth  to  one-half  will  usually  be 
burned;  sometimes  the  larger  part  will  be  burned.  The  individual 
factor  is  again  markedly  in  evidence.  If  urate  of  sodium  be  injected 
hypodermatically,  the  same  variable  results  will  be  secured.  In  each 
case  the  experiment  fails  to  approximate  the  normal  circumstances, 
since  a  large  mass  of  uric  acid  is  introduced  at  one  time;  and  it  is  possible 
and  indeed  probable,  that  under  such  circumstances  a  portion  will 
escape  transformation  that  might  have  been  transformed  if  it  had  been 
evenly  distributed  through  the  day.  Uricolytic  ferments  have  been 
demonstrated  in  the  liver,  spleen,  kidney,  muscles  and  bone  marrow. 
Uricolysis  is  undoubtedly  much  greater  in  the  carnivora  than  in  man, 
since  uric  acid  introduced  into  the  dog  is  practically  all  oxidized;  in 
man  the  fraction  is  small,  usually  less  than  half.  But  not  even  an 
approximate  measurement  of  this  uricolysis  can  be  accomplished  at 
present.  And  the  individual  factor  is  so  influential  in  the  purin  metab- 
olism that  it  would  not  be  permissible  to  apply  an  integral  factor  obtained 
as  the  means  of  a  series  of  observations;  where  a  mean  is  the  average 
of  a  series  of  widely  varying  individual  figures,  we  cannot  hope  to 
apply  it  to  an  individual  subject.  ♦ 

Mechanism  of  Uricolysis. — The  mechanism  of  this  uricolysis  is  not 
well  understood.  For  the  dog  and  cat  the  steps  of  oxidation  are  fairly 
well  known.  Allantoin  is  a  normal  constituent  of  the  urine  of  canines 
and  felines  and  is  said  to  occur  for  a  few  days  after  birth  in  the  urine 
of  cattle  and  of  infants.  As  its  name  indicates,  it  is  present  in  the 
allantoic  fluid.  It  is  said  to  occur  in  the  urine  of  pregnant  women 
and  occasionally  may  be  found  in  normal  urine.  It  must  be  admitted 
that  most  of  the  reports  on  the  occurrence  of  allantoin  have  come 
down  from  decades  ago,  and  recent  investigations  have  not  been  able 
to  confirm  the  reported  findings  of  allantoin  in  the  allantoic  fluid  of 
woman  or  in  the  urine  of  the  newborn.  The  formation  of  allantoin 
from  uric  acid  is  easily  accomplished  in  the  laboratory.  The  deriva- 
tion from  uric  acid  may  be  indicated  thus: 

Uric  acid  Allantoin 

HN  —  CO  HN  —  CH  —  NH 

Nco 


oi    A 


NH 

>co 

IN  —  C  —  NH  HN  —  CO 


OC 


NH2 


THE  CATABOLISM  OF  NUCLEIC  ACID  449 

The  intermediary  steps  are  unknown.    Allantoin  is  commonly  believed 
to  be  hydrolyzed  to  urea  and  glyoxylic  acid. 


Allantoin 

Urea 

Glyoxylic  acid 

HN  —  CH  —  NH 

^>CO  +  H20 

OC                   NH2 

1 

NH2 

=     2C  =  0 
NH2 

+ 

COH 
COOH 

HN  — CO 

In  the  carnivora  the  reaction  stops  at  the  stage  of  allantoin.  In  the 
rabbit  the  ingestion  of  uric  acid  is  apparently  followed  by  an  increase 
in  glycocoll,  which  could  have  been  derived  from  glyoxylic  acid.  In 
man  no  indications  of  this  reaction  are  to  be  seen.  The  human  tissues 
do  not  oxidize  allantoin  nor  do  they  form  allantoin  from  uric  acid,  as 
do  the  organs  of  the  dog. 

In  the  older  literature  one  finds  many  references  to  assumed  oxida- 
tion of  uric  acid  to  oxalic  acid;  this  needs  but  to  be  mentioned,  since 
it  is  devoid  of  foundation.  Despite  the  researches  of  four  decades  we 
do  not  yet  understand  the  oxidation  of  uric  acid  to  urea.  We  could 
bear  with  this  ignorance,  however,  if  we  but  knew  to  what  an  extent 
this  oxidation  occurs,  in  any  way  that  it  occurs.  The  writer  believes 
this  fraction  to  be  small,  but  is  fully  conscious  that  adequate  founda- 
tion for  the  opinion  does  not  exist. 

One  further  result  of  this  situation  is  that  we  may  make  no  inference 
of  exogenous  purin  from  the  output,  since  exogenous  uric  acid  like 
endogenous  uric  acid  is  subject  to  oxidation.  Under  these  circum- 
stances the  total  exclusion  of  exogenous  purin  from  the  diet  in  experi- 
ments directed  to  the  elucidation  of  any  feature  of  the  purin  metabolism 
is  imperative.  It  will  not  do  to  make  a  subtraction  for  the  exogenous 
purin. 

The  curve  of  the  endogenous  purin  is  quite  level,  being  higher  during 
the  day  than  at  night,  though  influenced  very  little  by  diet.  It  is  not 
influenced  by  sparse  or  copious  water  drinking,  by  acids  or  alkalies 
or  by  alcohol.  The  curve  of  the  exogenous  purins  follows  in  general 
the  periods  of  ingestion,  though  it  is  somewhat  prolonged.  Normally, 
the  purins  of  the  sweetbread  are  entirely  eliminated  within  twenty-four 
hours.  Under  conditions  of  health  the  body  no  more  tolerates  a  reten- 
tion of  purin  than  it  does  a  retention  of  protein. 

The  only  expression  of  the  purin  values  of  the  urine  are  the  masses 
of  uric  acid  and  bases.  A  ratio  of  uric  acid  to  urea  and  of  purin  nitrogen 
to  total  nitrogen  was  once  much  in  vogue.  Such  ratios  are  worthless. 
These  magnitudes  have  independent  variables,  and  cannot  therefore 
bear  a  ratio  to  each  other.  The  ratio  of  uric  acid  to  purin  bases  has 
a  valid  standing,  but  in  our  present  knowledge  we  are  able  to  attach 
little  importance  to  it.  It  is  easy  to  say  that  suboxidation  would 
increase  the  mass  of  purin  bases  at  the  expense  of  the  uric  acid.  This 
categorical  observation  has,  however,  little  value  so  long  as  the  postu- 
29 


450      METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

lated  variation  in  ratio  does  not  occur.  It  is  true  that  in  an  occasional 
case  of  nephritis,  the  amount  of  purin  bases  is  high.  It  is  also  seen  in 
occasional  intoxications,  and  in  some  febrile  infections.  When  the 
uric  acid  is  high  one  might  expect  to  see  the  purin  bases  high,  and  this 
is  often  the  case.  But  increased  purin  base  and  reduced  uric  acid  as 
the  expression  of  suboxidation  in  the  purin  metabolism  is  largely  a 
blackboard  proposition. 

It  is  not  known  in  what  state  the  purin  bases  circulate,  whether 
free  or  combined.  Since  their  mass  is  so  small,  the  matter  is  of  little 
consequence.  Uric  acid  circulates  in  but  one  form,  as  mono-urate. 
In  the  blood  are  ammonium,  sodium,  potassium  and  calcium,  all 
are  doubtless  in  combination  with  uric  acid,  in  proportion  to  their 
affinity  constants  and  in  relation  to  their  available  masses  in  the  system. 
There  is  little  ammonium  in  the  circulating  blood.  There  is  little 
potassium  and  a  great  deal  of  sodium  in  the  blood  plasma;  in  the  blood 
cells,  however,  the  potassium  predominates.  Certainly  the  largest 
fraction  of  the  circulating  uric  acid  is  combined  with  sodium.  Certain 
misconceptions  regarding  the  state  of  solubility,  combination,  and 
reaction  of  uric  acid  have  been  long  current  and  it  is  imperative  that 
the  correct  facts  be  emphasized,  though  this  is  not  the  place  to  enter 
into  physico-chemical  explanations  of  the  data.  Uric  acid  exists  in 
the  blood  only  as  the  mono-basic  salt;  it  cannot  exist  there  as  the 
di-basic  salt,  the  carbon  dioxid  alone  makes  that  impossible.  The 
existence  of  a  quadri-urate  is  entirely  a  blackboard  proposition,  there 
is  no  theoretical  foundation  for  it  and  no  experimental  proof  of  it. 
There  is  such  a  salt  as  a  bi-urate,  but  it  does  not  exist  in  the  circulating 
fluids  or  in  the  freshly  voided  urine.  It  is  not  probable  that  it  exists 
in  tophi  or  stones.  The  reaction  of  a  solution  of  monosodium  urate 
is  very  faintly  alkaline.  The  reaction  of  a  solution  of  disodium  urate 
would  be  more  strongly  alkaline,  but  as  stated  such  a  salt  is  not  stable 
in  solution  in  the  blood.  The  solubility  of  the  mono-urates  of  sodium, 
potassium  and  ammonium  depends  largely  upon  the  temperature, 
but  more  upon  the  form  of  uric  acid. 

Tautomeric  Forms  of  Uric  Acid. — Uric  acid  exists  in  two  tautomeric 
forms,  known  as  the  lactam  and  the  lactim  states.  The  lactam  state 
is  the  less  stable  and  the  more  soluble;  the  lactim  state  is  the  more 
stable  and  the  less  soluble,  and  the  uric  acid  in  solution  is  tending 
always  to  pass  into  the  lactim  state.  In  the  blood  both  states  co- 
exist, as  the  passage  from  one  state  to  the  other  is  slow  in  a  colloidal 
solution.  In  the  urine  in  all  probability  the  lactim  form  is  alone  to  be 
found.    These  tautomeric  forms  are  illustrated  in  equations. 

Lactam  form  Lactim  form 

HN  — CO  N  — C.OH 

OC        C  — NH  HO.C       C  — NH 

Yo  I 

/  I 

HN  —  C  —  NH  N  - 


THE  CATABOLISM  OF  NUCLEIC  ACID  451 

Solubility  of  Urates. — The  solubilities  of  the  three  salts  at  37°  in 
the  two  forms  are  as  follows. 

Lactam  state    Lactim  state 

Potassium  mono-urate 1  :  265  1  :  400 

Sodium  mono-urate 1  :  470  1  :  710 

Ammonium  mono-urate 1  :  1225         1  :  1850 

The  marked  difference  in  the  solubilities  of  the  three  salts  is  to  be 
noted,  and  also  the  fact  that  the  lactim  salts  are  much  less  soluble 
than  the  lactam  salts.  These  solubilities  of  the  salts  are,  however, 
very  much  greater  than  is  the  solubility  of  uric  acid,  which  at  37° 
is  1  :  15,000,  being  1  :  40,000  at  18°. 

Such  a  solubility  means  that  as  sodium  urate,  100  cubic  centimeters 
of  blood  plasma  would  hold  in  solution  at  the  temperature  of  the  body 
only  8  milligrams  of  the  lactim  form  and  18  of  the  lactam  form.  This 
is  not  in  harmony  with  experimental  facts.  One  can  get  ten  times  as 
much  monosodium  urate  into  solution  in  blood  plasma,  combined  in 
such  a  state  at  least  that  it  does  not  settle  down  or  precipitate  out.  It 
is  possible  that  this  urate  is  held  in  physical  adsorption  by  the  colloids. 
It  is  also  possible  that  it  is  held  in  complex  combination  with  the  traces 
of  pyrimidins  that  are  present  in  the  blood.  With  pure  solutions  in 
water  one  may  employ  physico-chemical  methods  of  measurement  to 
determine  whether  the  urate  is  in  solution;  in  the  blood  these  methods 
cannot  be  well  applied  with  accuracy.  On  account  of  the  concentration 
of  carbon  dioxid,  the  blood  is  practically  neutral  so  that  the  measure- 
ment of  the  electromotive  protential  leads  to  no  result,  as  the  potential 
of  the  urate  is  covered  up.  The  method  of  conductivity  cannot  be 
used  because  of  the  number  of  other  substances  there  present  that  are 
good  conductors;  and  the  slight  dissociation  of  the  urate  is  again 
covered  up.  But  if  blood  serum  be  shaken  with  sodium  urate  and 
allowed  to  stand  over  night  under  carbon  dioxid  pressure,  filtered  the 
next  day  and  the  uric  acid  of  the  clear  filtrate  determined,  it  will  be 
found  to  be  ten  times  as  much  as  water  would  have  dissolved  under  the 
same  circumstances. 

A  widespread  misconception  prevails  concerning  the  possibility  of 
altering  the  solubility  of  the  urate  in  the  blood  by  supposed  alteration 
of  the  reaction  of  the  blood — less  alkalinity  lowering  the  solubility, 
greater  alkalinity  increasing  the  solubility.  Now  there  is  in  the  blood 
no  alkaline  reaction  to  lower,  and  no  known  way  to  lower  it  if  it  were 
there  to  be  lowered.  There  is  perforce  no  alkaline  reaction  to  augment, 
and  no  way  to  increase  it  if  it  were  there  to  be  increased.  The  blood 
is  practically  neutral  and  with  the  greatest  tenacity  the  body  main- 
tains this  state  of  neutrality.  There  is  no  foundation  for  the  assumption 
of  a  lessened  solubility  of  the  urate  in  any  state  of  health  or  of  disease. 
And  there  is  no  foundation  for  the  assumption  that  the  solubility  of 
the  urate  can  be  increased  therapeutically.  There  is  in  the  body  no 
other  equilibrium,  not  even  the  body  temperature,  so  finely  adjusted 


452     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

and  so  perfectly  regulated  as  the  neutrality  of  the  blood.  If  the 
reaction  of  the  blood  could  be  increased  or  decreased  with  the  ease 
postulated  by  the  proponents  of  the  uric  acid  diathesis,  life  would  be 
impossible. 

Slight  as  is  the  solubility  of  the  urate  in  the  blood  plasma,  it  is 
vastly  in  excess  of  the  usual  requirements.  When  it  is  realized  that 
on  an  average  not  over  1  gram  of  uric  acid  is  eliminated  in  the  twenty- 
four  hours,  it  is  clear  that  in  any  one  moment  there  can  be  but  a  trace 
of  uric  acid  in  the  total  blood  of  the  body.  And  in  the  amount  that 
can  be  secured  for  analysis,  it  is  very  small  indeed.  This  all,  of  course, 
is  on  the  assumption  that  there  is  no  threshold  value  for  uric  acid. 
As  a  matter  of  fact,  it  is  very  difficult  to  prove  the  presence  of  any 
uric  acid  in  200  or  300  cubic  centimeters  of  normal  human  blood. 
When  this  can  be  done,  it  is  in  itself  a  pathological  finding.  There 
are  conditions  in  which  the  purin  output  is  very  greatly  increased, 
as  in  leukemia;  but  in  leukemia  the  blood  content  of  uric  acid  may 
be  so  low  as  again  to  baffle  demonstration — it  may,  however,  be  over 
0.010  per  100  c.c.  of  blood.  It  may,  therefore,  be  assumed  that  there 
is  normally  no  threshold  value  for  uric  acid;  apparently  the  kidneys 
attempt  with  uric  acid,  as  with  urea,  to  effect  a  complete  elimination. 
This  is  obviously  not  a  question  of  solubility,  it  is  a  question  of  the 
relations  of  urate  to  the  renal  cells.  Uric  acid  is  very  insoluble,  even 
in  the  state  of  the  most  soluble  urate;  urea  is  very  soluble.  But  for 
both  the  kidney  attempts  a  complete  elimination,  so  that  the  circulating 
fluids  are  practically  free  of  them. 

Eliminating  Power  of  Kidneys  for  Uric  Acid. — While  it  is  appar- 
ently true  that  there  is  not  a  threshold  value  in  the  kidney  for  uric 
acid,  and  direct  tests  in  nephritis  seems  to  indicate  that  it  is  not  a 
particularly  irritating  substance,  yet  there  appears  to  be  but  little 
leeway  in  the  power  of  eliminating  uric  acid,  and  an  increase  in  the  input 
that  must  be  termed  moderate  may  lead  to  accumulation  in  the  blood 
of  the  normal  individual.  A  meal  rich  in  sweetbread  may  lead  to  high 
values  of  uric  acid  in  the  blood,  up  to  5  milligrams  in  the  100  c.cm. 
The  accumulation  represents  a  stagnation;  the  uric  acid  is  poured  into 
the  blood  faster  than  the  kidneys  can  eliminate  it.  There  are  many 
pathological  illustrations  of  this  form  of  hyperuricemia.  When  one 
analyzes  the  figures,  it  becomes  clear  that  the  renal  power  of  elimina- 
tion of  uric  acid  tolerates  a  surprisingly  small  overload.  If  sweet- 
breads were  ingested  so  as  to  treble  the  total  amount  of  output  of 
uric  acid,  this  would  be  a  massive  input.  To  make  the  relations  quan- 
titative let  us  assume  that  all  the  extra  uric  acid  is  to  be  eliminated 
during  six  hours  following  the  ingestion,  and  that  during  this  six  hours 
the  total  uric  acid  of  the  sweetbreads,  2  grams  in  all,  will  be  gradually 
poured  into  the  blood.  If  all  this  uric  acid  were  to  be  poured  at  once 
into  the  circulating  blood,  it  would  correspond  to  a  concentration 
of  1  '•  6000,  far  below  the  solubility  of  monosodium  urate  in  water 
even,  in  which  the  urate  is  less  soluble  than  in  the  blood.    This  2000 


THE  CATABOUSM  OF  NUCLEIC  ACID 


453 


milligrams  would  be  eliminated  during  six  hours,  an  average  of  about 
5  milligrams  per  minute.  And  this  the  kidneys,  with  all  the  enormous  cir- 
culation they  possess,  often  cannot  accomplish  without  an  accumulation 
of  uric  acid  occurring  in  the  blood.  The  amount  of  blood  going  through 
the  two  kidneys  during  a  minute  must  be  very  large  and  would  contain 
many-fold  the  amount  of  uric  acid  that  is  eliminated  in  the  minute. 
While  there  is  not  normally  a  threshold  value  in  the  kidney  for  uric 
acid,  it  is  clear  that  the  permeability  (or  rather  power  of  elimination) 
of  the  kidney  for  uric  acid  is  very  low  and  tolerates  little  overload. 
It  is  possible  that  it  is  the  uric  acid  in  complex  combination  that 
resists  elimination,  but  that  would  really  mean  an  indirect  threshold 
value.  Exaggerated  input  of  exogenous  purin  is  the  only  physiological 
moment  that  is  known  to  raise  the  uric  acid  content  of  the  blood  to 
the  point  of  certain  chemical  demonstration,  which  may  be  set  at  a 
milligram  in  the  100  c.c.  of  blood.  It  must  not  be  inferred  that  exces- 
sive ingestion  of  exogenous  purin  is  always  followed  by  an  accumulation 
of  uric  acid  in  the  blood,  there  are  wide  individual  variations  in  this 
regard.  Noteworthy  also  is  the  fact  that  marked  increase  in  the  con- 
centration of  uric  acid  in  the  blood  does  not  seem  to  lead  to  increase 
in  uricolysis.  The  accumulated  mass  of  uric  acid  remains  in  the  blood 
for  a  number  of  hours,  during  which  time  the  kidneys  gradually  accom- 
plish its  elimination.  There  is  no  other  known  substance  in  relation 
to  which  this  peculiar  behavior  of  the  kidney  is  duplicated.  And  it 
is  important  for  the  correct  evaluation  of  the  data  bearing  on  the 
pathological  accumulation  of  uric  acid  in  the  blood  and  tissues,  that 
this  state  of  affairs  should  be  clearly  understood. 

The  factors  in  the  metabolism  of  the  purins  may  be  illustrated  in 
schematic  form  as  follows,  the  endogenous  purins  being  in  usual  type 
and  straight  lines,  the  exogenous  purins  underscored  and  in  dashed  lines. 


Input 


Metabolism 


Output 


Nucleic  acid 


Amino-and  oxy- 
pui  in  bases  "--..^ 

Uric  acid     •»„ 


Methyl-purins— 


Anabolism  of  nucleic  acid 


Catabolism  of  nucleic  acid 


Amino  and  oxy-purins 


Amino  and  oxy-puri 


^-4 

Catabolism. of  inosinic  acid  U 


Methyl  puiins        V-- 


"|  Methyl  purins  | 


From  this  chart  it  is  clear  that  the  estimation  of  the  uric  acid  or  the 
total  purin  of  the  urine,  cannot  be  regarded  as  an  index  of  the  total 
production  of  purin  (even  if  the  exogenous  purin  be  excluded)  or  of 
the  nucleic  metabolism. 


454     METABOLISM  OF  CREATIN-CREAT1NIN  AND  OF  PURIN 

The  following  schematic  chart  illustrates  the  relations  of  the  protein, 
purin  and  creatinin  metabolisms,  the  two  latter  being  represented  as 
free  of  exogenous  input,  exogenous  protein  being  intentionally  retained. 


Input 


Blood 

Exogenous 

protein 

input 


Metabolism 


Output 


Protein 
input-* 


PATHOLOGICAL   VARIATIONS   IN   THE   PURIN   METABOLISM 


Herein  are  included  variations  in  purin  anabolism;  variations  in  endog- 
enous purin  catabolism;  variations  in  the  exogenous  purin  catabolism; 
accumulation  of  purins  in  the  blood;  variations  in  uricolysis;  varia- 
tions in  the  urinary  output  of  uric  acid  and  in  the  curve  of  the  elimina- 
tion of  uric  acid ;  and  deposition  of  purins  in  tissues. 

Normally  there  is  but  one  cause  of  excess  of  purins  in  the  body, 
blood  and  urine — the  ingestion  of  excessive  exogenous  purins.  The 
results  of  such  excessive  ingestions  are  temporary,  and  lead  to  no 
derangement  of  the  nucleic  metabolism,  so  far  as  known.  Though 
the  renal  power  of  elimination  of  uric  acid  is  limited,  there  is  no  direct 
evidence  that  the  regular  and  even  excessive  ingestion  of  exogenous 
purins  (the  methyl  purins  excluded)  leads  to  renal  or  other  disease. 

There  are  no  known  variations  in  the  processes  of  nucleic  anabolism. 
In  the  most  excessive  multiplication  of  cells,  the  synthesis  of  purins  is 
apparently  fully  competent. 

Various  in  Endogenous  Purin  Catabolism. — In  all  conditions  in  which 
excessive  cell  destruction  occurs  in  the  body,  the  catabolism  of  purins 
must  be  excessive.  Leukemia,  pneumonia,  septic  leukocytosis,  internal 
collections  of  pus,  rapid  degenerations  of  tissues  as  sometimes  seen 
in  neoplasms,  and  acute  degeneration  of  the  liver  lead  to  excessive 
purin  catabolism.  Just  as  an  excess  of  ingested  nucleic  acid  is  catab- 
olized,  so  an  excess  of  endogenous  purins  is  catabolized.  In  leukemia 
we  may  observe  five  or  more  times  the  normal  magnitude  of  nucleic 
catabolism.  Both  uric  acid  and  the  purin  bases  are  increased  in  the 
urine,  the  uric  acid  most  of  all,  though  it  is  not  uncommon  to  find 


PATHOLOGICAL  VARIATIONS  IN  THE  PURIN  METABOLISM     455 

the  values  for  purin  bases  double  the  normal.  The  condition  is  most 
often  temporary,  but  in  leukemia  it  may  last  for  months.  When 
exogenous  purins  are  added  in  experiment,  they  too  are  elaborated 
in  the  usual  manner.  One  cannot  resist  the  impression  that  the  one 
weak  spot  in  the  whole  nucleic  metabolism  lies  in  the  function  of 
elimination  by  the  kidney. 

So  far  as  known  there  are  no  variations  in  the  endogenous  purin 
metabolism  in  gout.  The  term  "gout"  is  here  used  in  its  strict  sense, 
without  reference  or  relation  to  the  term  "uric  acid  diathesis."  This 
last-named  euphonious  expression  was  widely  used  for  several  decades 
as  a  cloak  for  ignorance.  But  just  as  fashions  in  furs  change  so  fashions 
in  the  cloak  of  ignorance  change;  and  the  uric  acid  diathesis  has  been 
lately  relegated  to  the  closet  for  old  clothes.  There  is  an  hypothesis 
that  the  total  purin  metabolism  is  reduced  in  gout.  This  hypothesis 
is  devoid  of  foundation  and  is  in  contradiction  to  our  best  knowledge. 
So  far  as  known  the  anabolic  and  catabolic  series  of  reactions  of  en- 
dogenous nucleic  acid  are  normally  carried  out  in  the  subject  of  gout. 
There  is  a  possibility  that  the  oxidation  of  uric  acid  is  reduced  in  gout. 
Uricolysis  is,  however,  not  to  be  regarded  as  a  portion  of  the  catabolism 
of  purins,  in  the  usual  sense  of  the  term.  If  we  are  to  use  this  term  in 
the  sense  of  including  the  oxidation  of  uric  acid,  then  in  man  the  normal 
catabolism  of  purin  is  largely  unfinished ;  and  certainly  the  term  ought 
not  to  be  used  in  this  sense. 

The  catabolism  of  the  total  exogenous  purins  can  be  shown  to  be 
retarded  in  gout.  Does  this  carry  with  it  the  inference  that  the  catab- 
olism of  the  endogenous  purins  is  retarded  in  gout?  The  possibility 
cannot  be  denied.  But  from  the  mere  fact  that  an  overload  cannot 
be  carried,  in  gout  as  well  as  in  health,  it  does  not  follow  that  the  normal 
load  cannot  be  carried.  The  increased  concentration  of  uric  acid  in 
the  blood  in  gout  would  naturally  lead  one  to  expect  the  catabolism 
of  the  purins  to  be  retarded.  But  in  other  conditions  in  which  equal 
increase  in  the  concentration  of  uric  acid  occurs  in  the  blood,  such  a 
retardation  is  not  observed.  Admitting,  therefore,  the  possibility  of 
such  a  retardation  in  gout,  there  is  no  proof  of  it. 

Variations  in  the  Catabolism  of  Exogenous  Purins. — In  gout  this  is 
distinctly  retarded,  though  qualitatively  normal.  A  sweetbread  ingested 
remains  in  the  metabolism  for  several  days,  instead  of  being  com- 
pletely catabolized  in  one  day  as  in  the  normal.  This  is  not  to  be 
observed  in  all  cases,  but  is  usual  in  the  event  of  symptomatic  gout. 
There  is  no  evidence  that  the  catabolism  is  incomplete;  it  merely 
requires  more  time  for  completion.  This  seems  to  be  characteristic  of 
gout. 

The  Blood  Content  of  Uric  Acid. — This  is  increased  as  a  constant 
condition  in  chronic  nephritis,  in  lead  poisoning,  in  gout,  and  in  some 
cases  of  leukemia;  temporarily,  it  occurs  in  pneumonia,  sepsis,  and 
following  the  excessive  ingestion  of  exogenous  nucleins  or  purins. 
It  may  be  as  high  as  G  to  10  milligrams  in  the  100  cubic  centimeters 


456     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

of  blood,  but  is  rarely  over  5.  But  5  milligrams  is  ten  times  the  normal 
concentration.  In  gout  this  persists  despite  starvation,  and  we  may 
assume  that  this  holds  for  the  other  chronic  diseases  named.  The 
several  conditions  are  to  be  divided  into  two  groups:  those  in  which 
the  increased  concentration  of  uric  acid  in  the  blood  is  the  result  of 
an  exaggerated  purin  catabolism,  due  either  to  exogenous  or  endog- 
enous purins;  and  those  in  which  there  is  no  increased  catabolism  of 
purins.  Nephritis,  lead  poisoning  and  gout  belong  to  the  last  group, 
all  the  others  to  the  first  group. 

Since  the  abnormal  concentration  of  uric  acid  in  the  blood  in  gout, 
lead  poisoning  and  nephritis  is  not  due  to  an  increased  formation  of 
uric  acid,  it  must  be  due  either  to  a  reduction  in  total  elimination,  or 
to  renal  impermeability.  That  there  is  retention  of  uric  acid  in  gout 
is  true,  since  tophi  are  formed,  which  is  not  the  case  with  lead  poison- 
ing and  nephritis.  But  the  amount  retained  is  so  slight — 10  milligrams 
per  day  would  account  for  all  the  tophi  in  a  gouty  body — that  this 
cannot  be  a  reason  for  the  increased  concentration  in  the  blood.  Obser- 
vations of  cases  of  gout,  nephritis  and  lead  poisoning  prove  that  the 
total  elimination  of  uric  acid  is  normal  in  time.  In  acute  gout,  as  will  be 
later  pointed  out,  there  are  fluctuations.  But  these  are  compensatory. 
Week  in  and  week  out  the  subjects  of  gout  eliminate  the  normal  amount 
of  uric  acid — minus,  of  course,  the  trivial  retentions  in  the  tophi.  There 
remains  but  one  explanation :  the  permeability  of  the  kidney  is  lessened. 
In  other  words,  a  threshold  value  has  been  established.  When  the 
blood  contains,  let  us  say  arbitrarily,  3  milligrams  of  uric  acid  per  100 
c.c.  blood  (this  will  vary  from  case  to  case  as  all  values  do  in  the  purin 
metabolism),  the  kidney  is  able  to  eliminate  the  full  amount  of  uric 
acid  formed  in  a  normal  manner.  A  similar  increase  in  the  threshold 
value  for  sugar  seems  to  occur  in  diabetes;  a  lowering  occurs  in  phloridzin 
poisoning.  We  are  able  to  give  no  explanation  for  this  phenomenon. 
It  is  not  due  to  nephritis,  as  the  term  is  ordinarily  used,  though  it 
occurs  in  practically  all  cases  of  sclerotic  nephritis.  Gout,  like  nephritis 
and  lead  poisoning,  causes  a  change  in  the  kidneys  whereby  the  threshold 
value  for  uric  acid  is  raised.  Only  when  the  concentration  of  uric  acid 
in  the  blood  is  increased  is  the  kidney  able  to  accomplish  the  normal 
quantitative  elimination.  The  fact  is  not  peculiar  to  gout  nor  does  it 
lead  to  gout;  it  is  rather  a  result  of  gout. 

Variations  in  Uricolysis. — Recent  investigations  tend  to  indicate 
that  in  gout  the  oxidation  of  uric  acid  is  reduced,  in  contradistinction 
to  lead  poisoning  and  nephritis.  The  demonstration  is  not  complete; 
it  cannot  be  convincing  until  we  have  a  procedure  wherewith  the  oxida- 
tion of  uric  acid  to  urea  can  be  measured.  That  the  catabolism  of 
nucleic  acid  to  the  stage  of  uric  acid  is  in  gout  retarded  in  time,  is  no 
proof  that  the  oxidation  of  uric  acid  is  retarded  or  lessened,  since  we 
are  dealing  with  independent  reactions.  The  increased  concentrations  of 
uric  acid  in  the  blood  ought  to  lead  to  increase  rather  than  decrease 
in  uricolysis,  other  factors  being  constant.    And  as  a  matter  of  fact,  in 


PATHOLOGICAL    VARIATIONS  IN  THE  PURIN  METABOLISM    457 

many  cases  of  gout  the  total  output  is  below  the  normal;  and  many 
competent  students  of  gout  regard  the  uricolysis  as  excessive  in  these 
cases,  assuming  of  course,  what  is  generally  conceded,  that  the  forma- 
tion is  normal.  One  must  not  follow  the  direct  lead  of  the  figure  of 
output.  The  output  of  uric  acid  is  often  low  during  the  few  days 
before  an  attack;  following  the  attack  it  rises,  and  the  excess  surpasses 
the  previous  retention.  Between  attacks  the  figure  may  be  low.  Now 
it  will  not  do  to  say  that  the  increase  following  the  attack  was  due  to 
decreased  uricolysis,  and  the  low  figure  between  attacks  was  due  to 
increased  uricolysis.  The  low  figure  between  attacks  may  have  been 
due  to  deposition,  the  high  figure  following  the  attack  to  resolution. 
The  blood  content  also  may  vary.  In  some  cases  the  total  added 
elimination  following  the  ingestion  of  sweetbread  is  less  than  expected; 
in  these  cases  an  increased  uricolysis  has  been  invoked.  How  varying 
are  the  experimental  data  is  shown  in  the  fact  that  in  one  case  of  gout 
the  direct  injection  of  urate  into  the  muscles  was  followed  by  a  normal 
and  quantitative  elimination.  Possibly  increased  or  decreased  uricolysis 
may  be  present  in  different  stages  of  the  disease;  but  of  crucial  impor- 
tance they  are  not.  And  in  any  event  the  stated  variations  have  not 
been  properly  established. 

Variations  in  the  Urinary  Output  of  Uric  Acid  and  in  the  Course  of  its 
Elimination. — Cases  of  gout  may  be  grouped  under  three  headings:  (a) 
In  many  chronic  cases  there  are  no  abnormalities,  (b)  In  most  acute 
cases  there  is  a  drop  in  the  output  of  uric  acid  before  the  attack,  fol- 
lowed by  a  marked  rise  in  elimination  after  the  attack,  (c)  In  some 
instances  there  seems  to  be  a  slight  reduction  in  the  regular  output  of 
uric  acid.  The  order  of  events  in  relation  to  the  acute  cases  could 
be  explained  by  the  assumption  of  an  increased  concentration  in  the 
system  prior  to  the  attack  or  even  between  attacks,  followed  by  elimina- 
tion subsequent  to  attack — the  increased  concentration  having  been 
possibly  a  factor  in  the  inauguration  of  the  attack,  the  sweeping-out 
a  factor  in  the  recession.  The  postulated  reduction  in  the  output 
between  attacks  has  been  explained  as  due  either  to  decreased  forma- 
tion, increased  uricolysis  or  deposition  within  the  tissues.  As  a  matter 
of  fact,  the  figures  for  this  reduced  elimination  are  not  convincing. 
In  any  event  the  amounts  concerned  are  small.  We  cannot  assume 
what  is  not  known — the  individual  standard  of  the  gouty  subject  in  the 
state  of  health.  All  of  the  figures  quoted  in  support  of  this  assumed 
reduction  in  elimination  may  be  duplicated  in  normal  urines.  On  the 
one  hand  we  see  the  variations  in  the  output  of  uric  acid  regarded 
as  the  cause  of  the  attack  of  gout;  on  the  other  hand,  we  might  regard 
them  as  the  result.  But  it  is  certain  that  the  same  variables  occur 
in  the  non-gouty,  without  the  production  of  any  of  the  results  supposed 
to  follow  in  their  train  in  the  subject  of  gout. 

The  Deposition  of  Urate  in  Tissues. — This  is  the  cardinal  feature  of 
gout,  though  it  is  certain  that  there  is  gout  without  any  urate  deposi- 
tion.    In  some  subjects  the  depositions  form  gradually,  without  any 


458     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

acute  symptoms.  In  many  cases  the  acute  attacks  centre  about  the 
local  deposition,  or  at  least  about  inflammation  surrounding  the 
local  deposition.  Here  lies  the  crux  of  the  situation  in  gout.  Two 
facts  are  certain.  Cartilage  tends  to  precipitate  urate  from  solution; 
and  the  local  deposition  in  gout  occurs  in  healthy  cartilage  (in  the 
kidney  and  liver  as  well)  and  not  as  the  result  of  necrosis  or  injury. 
The  tendency  of  cartilage  to  precipitate  urate  of  sodium  can  be  shown 
in  experiments  in  glass.  Cartilage  contains  a  great  deal  of  sodium; 
and  in  accordance  with  the  theory  of  solution,  if  saturated  solution  of 
sodium  urate  be  combined  with  a  solution  of  a  sodium  salt,  the  urate 
will  be  in  part,  precipitated.  Thus  a  saturated  solution  of  sodium 
urate  is  in  part  precipitated  by  the  addition  of  sodium  chlorid.  This 
factor  could  not  become  operative  except  with  saturation  of  sodium 
urate  in  the  blood,  a  condition  probably  attained  in  gout.  But  in 
leukemia,  nephritis  and  lead  poisoning  the  same  degree  of  saturation 
of  the  blood  with  urate  of  sodium  does  not  lead  to  the  precipitation 
of  urate  in  the  cartilages.  It  follows,  therefore,  that  there  must  be 
an  additional  factor.  This  factor  was  once  sought  in  necrosis  or  injury; 
the  latter  in  part,  to  explain  the  selection  of  certain  joints.  But  it  is 
clear  that  the  local  necrosis  is  the  result  and  not  the  cause  of  the  attack 
of  gout.  The  moment  or  factor  that  determines  the  precipitation  in 
cartilage  of  sodium  urate  from  the  blood  in  the  subject  of  gout,  in 
contradistinction  to  other  diseases  in  which  saturation  of  the  blood 
with  sodium  urate  is  equally  present,  is  not  known.  There  is  some- 
thing specific  in  gout;  the  attack  of  gout  is  not  a  mere  physio-chemical 
reaction.  Hyperuricemia  is  probably  necessary  for  the  occurrence  of 
an  attack  of  gout,  or  gout  of  any  kind;  but  all  cases  of  hyperuricemia 
are  not  gouty — there  is  some  specific  factor  that  makes  an  individual 
with  hyperuricemia  gouty.  Nor  can  the  difference  between  the  solubility 
of  the  lactim  and  lactam  forms  of  uric  acid  be  regarded  as  the  cause  of 
the  precipitation  of  urate  in  the  cartilages.  Equally  unknown  but 
especially  suggestive  of  a  specific  etiology  are  the  toxic  symptoms  of 
the  acute  attack  of  gout.  The  fever  and  other  toxic  symptoms  are 
not  to  be  explained  by  matters  of  concentration  of  urate  of  sodium  and 
the  deposition  thereof  in  small  tophi,  nor  by  the  occurrence  of  small 
areas  of  inflammation  in  cartilage.  The  fulminating  nature  of  some 
of  the  attacks  is  only  another  argument  for  a  toxic  basis.  That  this  lies 
in  the  toxicity  of  uric  acid  itself,  will  scarcely  be  advocated. 

It  is  scarcely  necessary  to  advert  to  the  older  view  that  variations 
in  alkalinity  bear  a  relation  to  the  attack  of  gout.  The  postulated 
decrease  in  alkalinity  would,  could  it  occur,  tend  to  dissolve  sodium 
urate,  not  precipitate  it.  As  a  matter  of  fact  the  reaction  of  the  blood 
and  cartilages  in  gout  is  neutral,  just  as  it  is  always  neutral  in  the  body. 
For  the  diagnosis  and  therapy  of  gout  two  facts  are  always  to  be  empha- 
sized: that  the  reaction  of  the  blood  and  tissues  is  not  altered  in  gout; 
and  that  the  amount  of  uric  acid  formed  in  catabolism  and  the  amount 


THE  METABOLISM  OF  PHOSPHORUS  459 

circulating  in  the  blood  cannot  be  learned  by  the  determination  of 
the  uric  acid  output  of  the  urine. 

For  the  immediate  present  it  is  clear  that  to  obtain  an  idea  of  the 
nucleic  metabolism,  the  purin  output  and  the  purin  content  of  the  blood 
must  be  determined  in  the  absence  of  exogenous  purin;  and  following 
this  the  velocity  of  the  exogenous  nucleic  catabolism  should  be  tested 
by  the  administration  of  sweetbread  and  the  determination  of  the  curve 
of  purin  elimination.  The  total  information  will  often  be  disappointing; 
but  as  yet  there  is  nothing  else  upon  which  we  may  found  an  opinion 
as  to  the  state  of  the  nucleic  metabolism. 


THE   FATE   OF   THE   PYRIMIDIN   BASES 

The  urine  contains  traces  of  cytosin  and  uracil.  Otherwise  these 
bases  seem  to  be  burned  in  the  body.  Of  the  relations  of  these  sub- 
stances in  the  catabolism  of  nucleic  acid,  we  know  nothing.  The  addition 
of  these  bases  to  a  solution  of  uric  acid  results  in  resistance  of  the  uric 
acid  to  precipitation,  and  from  this  it  has  been  inferred  that  a  complex 
between  the  pyrimidin  and  the  purins  has  been  formed.  As  stated  in 
another  section,  more  uric  acid  can  be  gotten  into  solution  in  blood 
serum  than  in  water.  This  may  exist  in  some  such  complex;  or  it  may 
be  held  in  adsorption.  An  hypothesis  for  the  explanation  of  the  pre- 
cipitation of  urate  in  gout  has  been  advanced  in  the  suggestion  that 
the  occasion  for  this  precipitation  lies  in  the  absence  of  the  pyrimidins 
with  which  the  uric  acid  forms  a  soluble  complex.  Experimental 
work  has  not  yielded  results  favorable  to  this  hypothesis.  On  the 
other  hand,  the  fact  that  uric  acid  will  dialyze  from  a  solution  in  blood 
serum  is  not  an  argument  against  its  existence  there  in  such  a  state 
of  complex.  There  would,  of  course,  be  an  equilibrium  in  the  two 
states :  sodium-urate-in-solution  and  sodium-urate-in-combination. 
Dialysis  would  lower  the  amount  of  sodium  urate  in  solution,  which 
would  be  followed  by  restoration  of  the  equilibrium  by  dissociation 
of  the  urate  in  complex  combination;  and  this  continuing,  urate  would 
dialyze  out  in  excess  of  the  amount  present  in  simple  solution.  The 
application  of  the  phase  rule  and  the  law  of  partition  would  also  make 
possible  the  dialyzation  of  uric  acid  from  a  system  in  colloidal  adsorp- 
tion. Adhering,  therefore,  to  the  view  that  sodium  urate  may  be  held 
in  the  blood  in  part  in  chemical  combination  or  physical  adsorption, 
there  is  no  evidence  that  the  defect  in  gout  lies  in  the  lack  of  these  in 
the  subject  afflicted. 


THE   METABOLISM   OF   PHOSPHORUS 

Phosphorus  exists  in  the  body  in  three  important  situations:     in 
organic  combination  in  nucleic  acid;  in  organic  combinations  in  the 


400     METABOLISM  OF  CREATIN-CREATININ  AND  OF  PURIN 

lipoids  of  the  central  nervous  system  and  elsewhere;  and  in  inorganic 
combination  in  the  skeleton.  Phosphorus  is  introduced  in  organic 
combination  in  the  nucleic  acids  and  phosphorized  lipoids  of  the  diet, 
and  as  inorganic  salts.  When  ingested  in  organic  combination  it  is 
set  free  in  the  processes  of  digestion;  and  all  phosphorus  is  apparently 
resorbed  in  the  inorganic  state.  Phosphoric  acid,  in  the  form  of  the 
salts  of  sodium,  calcium  and  magnesium,  constitutes  therefore  the 
substrate  of  the  anabolism  of  the  phosphorized  lipoids  and  the  nucleic 
acids. 

Phosphorus  is  eliminated  through  the  intestinal  tract  and  kidneys; 
there  is  no  cutaneous  elimination  of  phosphorus.  In  the  feces  are 
phosphates  and  residues  of  organically  combined  phosphorus.  In 
the  urine  are  phosphates  and  a  small  fraction  of  neutral  phosphorus, 
less  usually  than  100  milligrams  per  day  of  phosphorus.  The  renal 
and  intestinal  eliminations  of  phosphates  are  reciprocal.  Usually 
the  larger  fraction  passes  out  in  the  urine,  but  the  larger  fraction  may 
be  eliminated  in  the  stools.  The  presence  of  large  amounts  of  calcium 
and  magnesium  in  the  diet  tends  to  deflect  phosphates  from  the  urine 
to  the  feces.  There  are  no  known  metabolic  relation  concerned  in  the 
route  of  elimination. 

Assuming  that  the  phosphorus  content  of  the  skeleton  is  stationary 
and  that  the  phosphorus  output  of  the  central  nervous  system  is 
minimal,  the  phosphorus  output,  on  a  known  and  controlled  input, 
may  be  assumed  to  represent  the  intensity  of  the  nucleic  catabolism. 
A  phosphorus  balance  in  health  is  easily  secured;  and  it  is  fairly  certain 
that  the  amount  of  phosphorus  eliminated  daily  from  the  central 
nervous  system  is  very  small  and  quite  constant.  As  a  matter  of  fact, 
under  controlled  conditions,  the  total  phosphorus  and  the  total  purin 
outputs  tend  to  run  parallel ;  and  it  is  possible  that  adequate  and  supple- 
mentary data  may  indicate  that  the  total  phosphorus  elimination 
is  a  measurement  of  the  variable  of  nucleic  catabolism — something 
very  much  needed.  It  must  be  realized  that  control  of  the  phosphorus 
input  is  of  crucial  importance  in  such  investigations.  At  present  it 
seems  unlikely  that  with  the  nucleic  catabolism  assumed  as  constant, 
the  elimination  of  total  or  neutral  phosphorus  can  be  employed  as  a 
measurement  of  the  catabolism  of  the  substance  of  the  central  nervous 
system — the  amounts  involved  day  by  day  are  far  too  small. 


CHAPTER    VIII 

AUTOINTOXICATION 

The  specific  subject  of  autointoxication  does  not  lie  within  the 
scope  of  this  treatise.  Nevertheless,  reference  has  naturally  been 
made  under  different  headings  to  pathological  variations  definitely 
known  to  exist,  including  autointoxications.  It  is,  however,  permissible, 
in  this  connection  and  in  the  absence  of  a  systematic  survey  of  the 
subject,  to  state  the  point  of  view  in  the  problem  of  autointoxication 
that  must  be  entertained  by  the  student  of  metabolism.  The  student 
of  chemical  metabolism  naturally  occupies  a  more  conservative  posi- 
tion than  the  outposts  of  which  the  student  of  organ  function  has  taken 
possession.  He  requires  a  certain  association  between  signs  of  dis- 
turbed functionation  and  known  steps  and  stages  of  metabolism. 
It  is  for  him  not  enough  that  the  removal  of  an  organ  or  a  particular 
operative  interference  should  be  followed  by  a  symptom-complex, 
sometimes  clear-cut  but  often  very  indefinite.  It  is,  in  part,  because 
of  the  failure  to  attempt  to  correlate  in  a  specific  manner  these  symptom- 
complexes  with  established  data,  that  the  writings  on  the  theory  of 
hormones  and  the  literature  on  the  experimental  investigation  into  the 
interactions  of  internal  organs  present  such  a  mass  of  contradictions. 
It  is  clear  that  in  the  near  future  a  treatise  on  autointoxications  will 
be  written  on  the  basis  of  the  internal  functions  of  organs  in  the  light 
of  chemical  knowledge  of  metabolism. 

From  the  point  of  view  of  the  theory  of  metabolism,  there  are  a 
number  of  ways  in  which  an  autointoxication  may  be  established. 
But  in  the  very  beginning  it  is  necessary  to  define  the  term,  which  has 
been  used  so  loosely  as  to  have  almost  lost  concrete  meaning.  We 
may  define  the  term  by  what  it  does  not  contain  as  well  as  by  what 
it  does  contain.  Excluded  are  all  forms  of  exogenous  intoxication, 
such  as  arise  following  the  ingestion  of  known  or  undefined  toxic  sub- 
stances and  of  decomposed  food.  Excluded  are  all  intoxications  due 
to  decomposition  of  food  within  the  alimentary  tract;  and  all  infec- 
tions and  results  of  bacterial  life  here.  Bacteria  in  the  alimentary 
tract  may  in  one  of  three  ways  injure  the  organism  that  harbors 
them.  They  may  deprive  the  body  of  needed  components  of  diet.  No 
instance  of  such  action  has  yet  been  discovered,  but  such  action  might 
be  conjectured;  for  example,  if  bacteria  should  ferment  completely 
the  tryptophan  set  free  in  the  digestion  of  protein,  the  body  would 
be  unable  to  maintain  a  nitrogenous  equilibrium  and  eventually  would 
fail  in  protein  anabolism.  Bacteria  might  conceivably  alter  the  prod- 
ucts of  digestion  and  render  them  unavailable  for  the  processes  of 
anabolism.  Secondly,  bacteria  may  form  toxic  substances  in  the 
alimentary  tract  from  the  media  upon  which  they  are  maintaining  their 


462  A  UTOINTOXICA  TION 

existence,  just  as  bacteria  form  poisons  from  media  in  test-tubes. 
Thus  from  starch  large  amounts  of  butyric  acid  may  be  formed.  It 
is  known  that  normal  meat  undergoes  a  toxic  decomposition  in  the 
digestive  tract  of  the  animal  containing  a  culture  of  the  bacillus  of 
Gaertner.  To  what  extent  such  forms  of  bacterial  intoxication  occur 
is  not  known.  Lastly,  bacteria  may  intoxicate  through  the  develop- 
ment of  specific  infective  processes,  by  the  elaboration  of  specific 
toxic  substances.  The  infections  of  the  alimentary  tract  are  just  as 
exogenous  as  are  the  infections  of  internal  organs;  why  then  are  bacte- 
rial gastro-intestinal  infections  termed  autointoxications,  while  typhoid 
fever  and  meningitis  are  called  infectious  diseases?  It  is  not  possible 
as  yet  to  separate  into  clinical  classes  (or  even  in  the  laboratory)  the 
two  groups  of  diseases  resulting  from  bacterial  action  within  the  ali- 
mentary tract;  but  the  fact  that  none  are  autointoxications  should 
be  realized.  The  slight  bacterial  infections  of  the  intestinal  tract  are, 
in  fact  and  theory,  as  truly  microorganismal  infections  as  is  cholera. 

A  true  autointoxication  of  the  alimentary  tract  would  be  related 
to  increase  or  failure  of  a  secretion;  to  defect  in  the  digestive  processes 
associated  with  the  formation  of  a  toxic  agent;  or  to  the  evolution  of 
some  toxic  substance  from  the  foodstuffs  through  an  abnormal  quali- 
tative action  of  the  chemical  processes  of  digestion.  Thus,  hyper- 
chlorhydria  might  be  termed  an  autointoxication;  and  obstructive 
jaundice  is  a  typical  autointoxication  by  retention  of  an  end  secretion 
of  metabolism.  We  know  of  no  toxic  state  related  to  the  failure  of 
the  processes  of  digestion,  bacterial  action  being  excluded.  The  resorp- 
tion of  unaltered  foreign  protein  might  lead  to  anaphylactic  sensiti- 
zation. The  absorption  of  the  intermediary  stages  in  the  digestion  of 
protein,  such  as  peptone,  might  lead  to  intoxication  if  not  nullified  in 
the  resorption  membrane.  We  know  of  no  abnormal  qualitative 
deflection  in  the  chemical  reactions  of  digestion  whereby  poisons  are 
formed  from  the  foodstuffs.  Future  investigations  may  indicate  that 
such  exist.  But  when  one  recalls  that  the  processes  of  digestion  are 
hydrolytic  cleavages  and  lead  to  the  splitting  of  the  large  molecules 
of  the  foodstuffs  into  simpler  preformed  components,  it  is  difficult  to 
understand  how  any  qualitative  deflection  could  result  in  the  forma- 
tion of  toxic  substances.  In  the  reconstruction  processes  in  the  wall 
of  the  small  intestine  lie,  however,  possibilities  for  the  origination  of 
toxic  substances — a  theoretical  possibility  for  which  we  have  no  evidence 
of  actual  occurrence. 

Inside  the  body  the  possible  modes  for  the  development  of  true 
autointoxications  are  clearly  outlined  by  our  knowledge  of  metabolism. 
We  may  state  the  possibilities  under  several  headings: 

Autointoxication  by  retention  of  end  products  of  metabolism. 

Autointoxication  by  incompletion  of  reaction  series,  whereby  an  inter- 
mediary product  becomes  an  end  product  or  accumulates  in  the  body. 

Autointoxication  through  the  failure  of  reactions  of  distoxication. 

Autointoxication  through  the  formation  of  a  qualitatively  abnormal 
substance  in  the  metabolism. 


A  UTOINTOXICATION  463 

Autointoxication  through  quantitative  variation  in  a  normal  sub- 
stance. 

While  it  is  clear  that  many  well-known  clinical  states  of  autointoxica- 
tion (such  as  aseptic  fever,  the  complex  that  follows  extensive  cuta- 
neous burns,  the  condition  associated  with  exposure  to  high  tempera- 
ture, Addison's  disease,  the  cachexia  of  thyroidectomy,  parathyroid 
tetany,  idiopathic  tetany,  myxedema,  etc.)  cannot  be  elucidated 
now  upon  any  such  basis,  illustrations  are  at  hand  for  each  of  these 
classes,  either  clinical  or  experimental.  These,  with  the  restriction 
in  the  use  of  the  data  and  concepts  necessitated  by  our  knowledge  of 
metabolism,  will  be  briefly  sketched. 

Autointoxication  by  Retention  of  End  Products  of  Metabolism. — To  the 
view  of  the  lay  mind,  this  has  always  been  a  natural  concept  of  self- 
intoxication,  since  with  the  psychological  aversion  usually  displayed 
toward  the  excrementa,  the  idea  that  they  were  of  poisonous  nature 
became  universal.  To  the  student  of  metabolism,  it  was  much  more 
logical  to  assume,  for  the  urine  at  least,  that  the  processes  of  metabolism 
would  tend  to  the  final  production  of  end  products  of  innocuous  nature. 
The  feces  on  account  of  the  bacteria  they  contain  are  in  a  sense  foreign 
to  the  body.  As  a  matter  of  fact,  with  one  exception  we  are  not  now 
in  possession  of  information  connecting  any  known  autointoxication 
with  any  end  product  of  catabolism;  and  with  this  one  exception, 
the  end  products  of  catabolism  are  known  to  be  relatively  if  not 
absolutely  innocuous. 

The  end  products  of  catabolism  contained  in  the  expired  air  are 
carbon  dioxid  and  water,  under  normal  conditions.  The  expired  air 
contains  no  nitrogenous  substance.  It  may  contain  volatile  bodies 
from  the  diet — such  as  alcohol,  essential  oils  from  spices  and  vegetables, 
aldehyds  from  fruits — it  may  contain  volatile  products  of  the  fat 
metabolism  (such  as  acetone  and  probably  aldehyd-like  substances); 
but  the  elimination  of  end  products  of  metabolism  apart  from  carbon 
dioxid  and  water  does  not  occur  by  this  route  so  far  as  known.  In 
direct  disagreement  with  these  statements  are  popular  ideas  on  the 
effects  and  symptomology  of  contaminated  air.  It  has  been  lately 
shown  that  the  expired  air  of  one  species  can  sensitize  an  animal  of 
another  species  following  parenteral  introduction.  This,  however,  is 
a  specific  protein  reaction,  and  can  have  no  relation  to  the  vitiation 
of  air  by  human  beings  for  human  beings.  When  the  effects  of  the 
breathing  of  over-respired  air  are  analyzed,  a  number  of  different 
elements  are  presented.  The  air  is  warmer  and  the  humidity  greatly 
increased.  There  are  the  odors  of  the  cutaneous  secretions,  which 
rapidly  undergo  bacterial  decomposition.  There  are  the  artificial 
odors  of  fashion,  often  even  more  distasteful.  Lastly,  there  is  the 
pronounced  psychic  or  esthetic  effect  seen  in  the  refined  classes,  usually 
more  pronounced  in  women  than  in  men.  Wliosoever  would  rest  the 
influence  of  over-respired  air  upon  purely  chemical  grounds  must 
explain  in  some  way  the  entire  absence  of  the  supposedly  pathognomonic 
symptoms  in  men  who,  in  dense  crowds,  frequent  political  meetings 


404  AUTOINTOXICATION 

and  drinking  quarters.  Doubtless  reduction  of  oxygen  and  increase 
in  carbon  dioxid,  promoting  more  rapid  respiration,  do  exaggerate 
the  action  of  the  above-named  influences,  though  there  is  no  evidence 
of  real  oxygen  hunger  or  carbon  dioxid  congestion  in  the  crowded 
rooms  with  which  we  are  acquainted  in  modern  life.  As  to  the  air 
of  theaters,  now  so  much  under  discussion,  it  is  certain  that  vitiation 
proceeds  less  from  the  audience  than  from  the  stage.  •  It  is  possible 
that  future  studies  may  demonstrate  in  the  expired  air  highly  toxic 
substance  of  volatile  nature  in  extreme  attenuation.  But  for  the 
present  we  have  no  metabolic  conception  of  such  toxic  volatile  sub- 
stances and  no  chemical  data  that  in  any  way  afford  presumption 
of  their  existence. 

The  skin  is  an  organ  of  elimination  of  end  products  of  the  nitrogenous 
catabolism.  Whether  these  are  only  incidentally  eliminated,  like 
the  salts,  in  association  with  the  elimination  of  water;  or  whether  the 
elimination  is  a  true  specific  secretory  function,  is  not  known.  The 
present  data  favor  the  interpretation  of  elimination  as  an  incidental 
secretion.  The  amounts  concerned  are  not  large,  though  they  include 
all  the  nitrogenous  end  products.  The  elimination  is  not  variable 
except  as  the  output  of  water  is  variable;  it  rises  with  the  water  out- 
put, falls  with  the  water  output,  and  the  usual  elimination  (0.2  to  0.3 
gram  N)  represents  the  unconscious  perspiration.  The  so-called 
vicarious  action  of  the  skin  for  the  kidneys  has  failed  of  concreted 
demonstration.  Of  course  the  nephritic  subject  will  eliminate  more 
nitrogenous  end  products  on  forced  sweating;  so  does  the  normal  subject. 
That  even  under  conditions  of  increased  concentration  of  nitrogenous 
end  products  of  metabolism,  exceptionally  large  eliminations  occur 
through  the  skin,  naturally  or  provoked,  is  difficult  of  demonstration. 
Crusts  of  urinary  salts  have  long  since  ceased  to  form  upon  the  dry 
skin  of  patients  with  uremia.  In  any  event,  an  increased  elimination 
would  be  expected,  in  accordance  with  the  law  of  diffusion,  from  subjects 
whose  blood  contains  an  increased  concentration  of  these  substances, 
both  in  natural  and  in  provoked  sweating.  It  is  possible  that  future 
investigations  may  reveal  in  the  cutaneous  secretions  highly  toxic 
substances  in  great  attenuation,  but  we  have  no  data  tending  to  suggest 
such  an  elimination.  The  autointoxication  that  follows  superficial 
burns  of  wide  extent  is  not  dependent  on  reduction  in  the  function  of 
cutaneous  elimination. 

Obstructive  jaundice  is  a  perfect  illustration  of  an  autointoxica- 
tion through  retention  of  the  end  products  of  metabolism.  Whether 
the  toxic  action  reside  solely  in  the  biliary  salts  and  pigment,  or  is 
to  some  extent  related  to  the  other  bodies  contained  in  bile,  as  to  the 
lipoids,  is  not  known. 

The  end  products  of  metabolism  eliminated  in  the  urine  have  long 
been  invoked  as  the  causative  factors  in  autointoxication,  especially 
in  uremia.  It  must  be  admitted  that  there  are  no  gaps  in  the  attempts 
to  lay  uremia  at  the  door  of  the  end  products  of  the  nitrogenous  catab- 
olism.    In  historic  succession  uremia  has  been  attributed  to  urea, 


A  UTOINTOXICA  TION  465 

to  ammonia,  to  the  purins,  to  creatinin,  and  now  the  attempt  is  being 
made  to  relate  it  to  the  rest-nitrogen.  It  is  true  that  in  some  of  the 
stages  of  nephritis,  one  or  all  of  these  may  be  retained.  Such  periods 
of  retention  are  the  results  of  nephritis;  there  is  no  evidence  that  the 
substances  retained  provoke  uremia,  there  is  indeed  the  best  evidence 
to  the  contrary.  The  rest-nitrogen  is  apparently  the  hardest  to  elimi- 
nate, and  it  is  perhaps  always  retained  to  some  extent  in  nephritis, 
apparently  with  an  increased  threshold  value  in  the  blood.  But  there 
is  no  evidence  that  the  substances  included  in  the  rest  nitrogen  are 
the  toxic  causes  of  uremia.  The  salts  of  potassium  were  once  incrimi- 
nated; now  it  is  the  chlorion.  Of  course  a  toxicity  may  under  forced 
conditions  be  demonstrated  for  each  of  these  substances;  but  such  a 
toxicity  may  not,  with  our  present  clinical,  chemical  and  experimental 
information  on  uremia,  be  invoked  as  the  etiological  factor  in  this 
intoxication.  The  retentions  and  the  uremia  may  go  hand  in  hand, 
fellow-results  of  nephritis ;  but  they  do  not  always  occur  together,  there 
is  retention  without  uremia,  there  is  uremia  without  retention.  To 
appeal  finally  to  the  summation  of  the  toxic  actions  of  these  several 
substances  as  the  cause  of  uremia,  is  begging  the  question.  The  cause 
of  uremia  is  as  unknown  today  as  in  the  day  of  Bright. 

Autointoxication  by  Incompletion  of  a  Reaction  Series,  Whereby  an 
Intermediary  Product  Becomes  an  End  Product  and  Accumulates  in  the 
Body. — From  the  standpoint  of  theory,  this  aspect  of  the  question  of 
autointoxication  offers  much  promise.  The  ketonic  intoxication  of 
diabetes,  the  acidosis  of  b-oxy-butyric  and  acetoacetic  acid  (our  best- 
known  autointoxication)  is  of  this  nature.  The  series  of  reactions 
of  combustion  is  incompleted  and  the  body  is  flooded  with  the  ketonic 
acids  that  abstract  bases  from  the  tissues  and  exhibit  their  own  toxic 
properties.  The  body  attempts  to  nullify  this  by  the  reduction  of 
acetoacetic  acid  to  acetone,  and  outside  of  diabetes  often  and  in  diabetes 
for  long  periods  of  time  succeeds;  but  this  reaction  all  too  often  fails, 
and  autointoxication  results.  Cystinuria  represents  such  a  situation 
chemically,  but  there  is  no  toxicity  of  the  intermediary  product.  Under 
the  commonly  prevailing  view  of  alcaptonuria,  the  homogentisic  acid 
is  regarded  as  an  unoxidized  intermediary  substance,  again  however, 
without  toxicity.  One  of  the  most  recent  hypotheses  of  the  cause  of 
fever  attributes  to  unoxidized  purin  bases  a  toxic  action  upon  the 
heat  centre — without  justification  in  the  opinion  of  the  writer.  Cholin, 
a  very  toxic  base,  is  normally  set  free  in  the  catabolism  of  the  white 
matter  of  the  central  nervous  system.  It  is  in  some  way  catabolized, 
for  it  is  not  present  in  normal  urine,  at  least  in  more  than  infinitismal 
traces.  But  in  conditions  of  widespread  degeneration  of  the  central 
nervous  system,  more  cholin  is  set  free  than  can  be  transformed,  and 
it  appears  in  blood  and  urine  free.  Possibly  some  of  the  symptoms  of 
these  nervous  diseases  may  be  due  to  the  toxic  action  of  the  excessive 
amounts  of  cholin,  though  this  is  not  demonstrated.  The  flooding  of 
the  blood  with  lactic  acid  in  phosphorus  poisoning  represents  another 
instance  of  the  appearance  in  the  system  of  an  intermediary  product. 
30 


466  AUTOINTOXICATION 

Hematoporphyrin  is  the  intermediary  substance  in  the  formation  of 
bilirubin,  and  is  present  in  the  urine  in  many  states  of  intoxication. 
And  finally,  the  symptoms  of  the  dog  with  Eck  fistula,  according  to 
the  most  recent  investigation,  may  under  certain  circumstances,  be 
related  to  an  alkalosis,  again  an  incompleted  reaction.  A  reaction 
series  may  be  checked  in  one  of  two  ways:  either  a  substance  or  fer- 
ment or  other  condition  necessary  for  a  particular  stage  is  lacking; 
or  some  substance  enters  and  by  combination  with  an  intermediary 
body,  effects  its  withdrawal  from  further  reaction.  It  is  after  the 
last-named  fashion  that  acids  check  the  formation  of  urea  from 
ammonia,  that  benzoic  acid  checks  the  oxidation  of  glycocoll,  that 
sulphuric  acid  checks  the  oxidation  of  normal  phenol.  The  occurrence 
of  cystinuria,  alcaptonuria  and  of  ketonic  acidosis  cannot  be  explained 
on  this  basis;  here  some  conditions  essential  to  the  reaction  have  failed 
or  become  inoperative.  It  is  certain  that  future  investigations  will 
find  this  a  fertile  field  for  studies  in  autointoxications. 

Autointoxication  through  Failure  of  Reactions  of  Distoxication. — This 
is  a  most  probable  cause  of  autointoxication,  though  little  work  has 
been  done.  The  infectious  diseases  are  recovered  from  through  what 
amounts  to  a  reaction  of  distoxication,  the  reaction  of  immunity. 
The  body  protects  itself  from  innumerable  exogenous  poisons,  when 
administered  by  the  mouth,  by  reactions  of  distoxication.  Metals 
are  eliminated  distoxicated  in  the  state  of  some  organic  combination 
that  is  undissociated.  Foreign  organic  substances  are  combined  with 
metabolic  components  so  as  to  render  them  innocuous,  good  illustra- 
tions being  the  conjugations  of  phenol  and  camphor  in  the  liver.  Under 
these  circumstances  it  would  seem  certain  that  similar  reactions  occur 
within  the  domain  of  metabolism.  Recent  very  suggestive  investiga- 
tions on  variations  in  the  toxic  action  of  acetonitril  indicate  extremely 
close  relations  between  metabolic  states  and  distoxication  (or  tolera- 
tion) of  toxic  bodies.  It  may  well  be  queried  if  such  are  not  frequently 
present  between  metabolism  and  product  of  metabolism.  Possibly 
the  interactions  of  internal  organs  are,  in  part,  to  be  elucidated  upon 
some  such  basis.  Why  should  not  the  actions  of  hormones  lie  in  the 
direction  of  distoxication  as  well  as  in  the  direction  of  stimulation? 
Certainly  the  field  promises  much  to  research. 

Intoxication  through  the  Formation  of  Qualitatively  Abnormal  Substances 
in  the  Body. — When  one  considers  the  number  of  labile  organic  sub- 
stances in  the  body,  which  is  a  chemical  reaction-system,  the  wonder 
is  that  qualitative  deflections  do  not  occur  more  frequently.  Under 
the  most  recent  interpretation  of  the  origination  of  alcapton,  this 
substance  is  not  to  be  regarded  as  a  normal  intermediary  body,  but 
rather  as  an  abnormal  substance.  If  we  regard  the  pentose  in  idio- 
pathic pentosuria  as  derived  from  glucose,  this  constitutes  a  reaction 
with  the  production  of  an  abnormal  substance,  since  the  normal  pentose 
of  the  nucleic  acid  is  not  the  same  as  the  pentose  that  is  formed  and 
eliminated  in  this  disease.  We  know  of  no  clinical  autointoxication 
in  which  the  formation  of  a  new  substance  has  been  definitely  estab- 


A  UTOINTOXICA  TION  467 

lished;  but  the  field,  for  reasons  of  methods  as  well  as  for  reasons  of 
view-point,  has  not  been  even  superficially  explored. 

Autointoxication  through  Quantitative  Variation  in  the  Production  of 
a  Normal  Substance. — We  have  many  illustrations  of  such  exaggerations 
in  the  quantitative  flow  of  metabolism,  but  so  far  no  definite  auto- 
intoxication has  been  founded  thereon.  In  leukemia  there  is  an  enor- 
mous exaggeration  in  the  catabolism  of  nucleic  acid;  but  the  presence 
in  the  body  of  the  purins  even  in  these  amounts  does  not  appear  to 
intoxicate.  In  a  similar  manner,  in  conditions  of  great  exaggeration  of 
the  protein  catabolism,  the  end  products  of  this  function  are  strikingly 
increased.  The  body  evidently  tolerates  a  large  overload  in  normal 
function  and  in  the  concentration  of  normal  substances.  Possibly 
aseptic  fever  may  be  ranged  with  this  type  of  autointoxication,  due 
to  huge  exaggeration  in  certain  disintegration  products  of  cells. 

To  estimate  properly  any  concept  of  autointoxication,  the  role  of 
compensation  and  adaptation  in  physiological  and  chemical  functiona- 
tion  must  be  borne  in  mind.  Organic  lesion  usually  does  not  produce 
disturbance  in  total  chemical  function;  an  overload  is  tolerated,  a 
deficiency  is  put  up  with.  Just  as  we  must  not  expect  alterations 
in  chemical  function  with  all  lesions  of  the  glandular  organs;  so  we 
must  not  expect  autointoxication  with  all  disturbances  in  metabolism. 
Autointoxication  may  be  immediately  related  to  slight  metabolic 
disturbance;  it  may  never  appear  with  a  gross  variation.  So  much 
depends  upon  the  specificity  of  the  particular  function,  upon  the 
chemical  properties  and  relations  of  the  substance  concerned.  A 
chemist  contemplating  urea  would  not  expect  it  to  be  a  toxic  agent; 
looking  at  histidin  or  cholin  he  would  expect  them  to  be  the  substrates 
of  reactions  whereby  highly  toxic  agents  could  be  easily  evolved.  This 
is  a  point  of  view  necessary  to  the  successful  approach  to  the  problem 
of  autointoxication. 

There  are  other  forms  of  apparent  auto-intoxications  that  are  not  to 
be  classified  at  present.  The  secretions  of  the  intestine  and  of  the  pan- 
creas are  toxic  on  parenteral  introduction,  the  pancreatic  juice  particu- 
larly so.  The  action  of  bacteria  can  be  ruled  out,  in  the  infective  sense, 
and  possibly  in  the  chemical  sense  also.  The  symptoms  of  the  intoxi- 
cations appear  quickly  after  the  introduction  of  the  secretions,  so  quickly 
as  to  make  it  doubtful  if  the  ill  effects  could  be  the  results  of  the  mani- 
festation within  the  body  of  the  enzymic  properties  of  the  secretions. 
Whether  these  toxic  properties  are  to  be  related  to  a  metabolic  end 
product  or  to  a  specific  secretion,  has  not  been  determined.  What 
relation  the  toxic  properties  bear  to  the  clinical  diseases  of  the  alimen- 
tary tract  is  entirely  problematical.  It  is  possible  that  these  unchanged 
secretions  could  be  resorbed  under  abnormal  conditions.  It  is  possible 
that  some  results  of  intestinal  obstruction  may  be  due  to  the  resorption 
of  the  secretions.  It  is  possible  that  the  symptoms  of  acute  pancrea- 
titis may  be  due  to  resorption  of  the  secretion.  The  available  data  do 
not  warrant  an  opinion  upon  these  questions. 


"APTER    IX 

METABOLISM   CONSIDERED  AS  A  WHOLE 
GENERAL   RELATIONS    OF   METABOLISM 

When  one  contemplates  the  metabolic  transformations  in  animals, 
it  becomes  clear  that  we  are  concerned  with  two  main  factors.  There 
is  firstly,  a  relation  of  metabolic  transformation  to  mass  of  tissue, 
and  this  relation  is  one  of  direct  proportionality.  There  is  secondly, 
a  coefficient  of  metabolic  intensity,  and  this  is  according  to  modern 
conceptions  to  be  related  to  the  factor  of  the  enzyme.  The  coopera- 
tion of  these  two  factors,  in  different  animals,  results  in  the  biological 
condition  that  different  species  have  widely  varying  planes  of  total 
metabolic  transformation.  There  are  animals  whose  plane  of  metab- 
olism and  growth  is  tenfold  that  of  man ;  there  are  animals  whose  plane 
of  metabolism  and  growth  is  greatly  below  that  of  man.  Within  the 
species,  variations  in  these  two  factors  bring  about  individual  varia- 
tions in  the  metabolic  processes.  We  are  not  able  to  determine  accu- 
rately, or  even  approximately,  in  an  individual  the  mass  of  cellular 
tissue,  since  build  of  skeleton,  deposition  of  fat  and  water  content  are 
widely  variable.  From  this  point  of  view  alone,  we  would  not  expect 
two  bodies  of  the  same  kilo  weight  or  surface  area  to  present  identical 
figures  for  metabolism.  These  variations  disregarded,  however,  it 
is  furthermore  clear  that  variations  in  the  coefficient  of  metabolic 
intensity  must  lead  to  variations  in  metabolism  from  individual  to 
individual.  Herein  lies  probably  a  variable  more  often  and  more 
strikingly  operative  than  variation  in  the  ratio  of  cellular  tissue  to 
total  weight.  This  variation  lies  in  the  amount  or  conditions  of  opera- 
tion of  the  enzymes.  Some  bodies  produce  more  enzyme,  or  the  condi- 
tions of  fermentation  are  favorable;  other  bodies  produce  less  ferment, 
or  the  conditions  of  enzyme  action  are  unfavorable.  In  a  word,  we 
have  represented  in  individuals  the  two  factors  of  substrate  concen- 
tration and  enzyme  concentration,  and  must  expect  to  observe  in  the 
results  the  operations  of  the  laws  of  mass  action  and  of  catalytic 
acceleration. 

It  is  possible  in  a  roughly  approximate  manner  to  obtain  a  notion 
of  the  relation  of  mass  of  metabolic  tissue  to  transformation  in  the 
unit  of  time.  The  total  energy-content  of  a  body  of  70  kilos  in  normal 
flesh  may  be  estimated  at  150,000  Calories.  The  basal  heat  produc- 
tion of  such  a  body  would  be  about  1800  Calories  per  day,  in  other 
words  a  daily  transformation  of  1.2  per  cent.    This  basal  heat  produc- 


THE  SPECIFIC  DYNAMIC  ACTION  OF  FOODSTUFFS        469 

tion  of  the  fasting  and  resting  body  is  set  free  largely,  if  not  entirely, 
by  reactions  of  combustion  in  the  muscular  system.  The  mass  of 
muscular  system  in  such  a  body  would  be  not  over  30  kilos.  Each  kilo 
of  muscle  substance,  therefore,  transforms  daily  into  water  and  carbon 
dioxid  about  15  grams  of  glucose  with  the  production  of  60  Calories 
of  heat.  At  heaviest  work  each  kilo  of  muscle  can  burn  per  day  100 
grams  of  glucose,  with  the  evolution  of  some  400  Calories  of  heat. 

The  total  protein  content  of  a  body  of  70  kilos  may  be  estimated  at 
12  kilos.  The  basal  cellular  protein  metabolism,  as  will  be  detailed 
in  this  chapter,  may  be  set  at  40  grams  of  protein  per  day,  a  daily 
transformation  of  J-  per  cent. 

The  total  protein  content  of  the  muscular  system  may  be  estimated 
at  8  kilos.  The  creatinin  elimination  of  such  a  body  may  be  set  at  2 
grams.    The  transformation  coefficient  is,  therefore,  about  4000 : 1 . 

The  total  nucleic  acid  content  of  the  body,  very  roughly  estimated 
from  the  purin  and  pentose  content  of  tissues,  may  be  set  at  60  grams. 
The  daily  purin  output  of  the  body  on  the  minimal  ration  of  protein 
may  be  set  at  about  0.3  gram  per  day,  a  transformation  of  a  little 
over  1  per  cent.  From  these  figures  we  may  infer  that  the  intensity  of 
metabolism  is  greatest  in  the  nucleic  and  least  in  the  creatin-creatinin 
metabolism. 

In  all  these  calculations  the  conversions  of  purins  and  creatinin 
into  urea  have  been  disregarded. 

These  coefficients  of  reaction  velocity  are  to  be  regarded  as  specific 
to  the  particular  chemical  reaction  involved.  And  the  figures,  though 
only  approximate,  give  us  some  idea  of  the  relations  of  mass  of  tissue 
to  metabolic  transformation  under  normal  conditions  of  ferment 
concentration. 


THE    SPECIFIC   DYNAMIC    ACTION    OF    FOODSTUFFS 

The  heat  production  of  an  animal  depends  to  a  large  extent  upon 
the  external  temperature.  There  is,  of  course,  as  will  be  later  elucidated, 
a  certain  production  of  heat  that  is  maintained  even  when  the  body 
is  living  in  an  atmosphere  whose  temperature  equals  or  exceeds  that 
of  the  body.  But  below  this  point,  the  production  of  heat  depends 
in  large  part  upon  the  difference  between  the  external  and  the  body 
temperature.  If  the  skin  were  a  perfect  insulation,  this  adaptation 
would  lie  within  much  narrower  limits,  since  then  apart  from  warming 
the  food  and  drink,  the  only  needs  for  extra  heat  production  would  be 
for  evaporation  of  water  from  the  lungs  and  the  warming  of  the  inspired 
air.  In  certain  marine  animals  the  body  probably  operates  upon  this 
basis,  which  explains  their  ability  to  live  in  cold  water  whose  abstrac- 
tion of  warmth  would  otherwise  make  enormous  demands  upon  the  pro- 
duction of  heat.     In  the  earlier  days  of  metabolic  experimentation,  the 


470  METABOLISM  CONSIDERED  AS  A   WHOLE 

reactions  of  the  body  of  the  animal  under  experimentation  were  studied 
without  reference  to  the  external  temperature.  It  is  now  clear  that 
this  factor  of  external  temperature  is  of  enormous  importance  in  deter- 
mining the  metabolism  of  an  animal.  Under  certain  conditions  the 
ingestion  of  food  may  be  followed  by,  or  associated  with,  an  exaggera- 
tion of  the  production  of  heat,  i.  e.,  the  reactions  of  combustion  are 
increased  on  the  ingestion  of  food.  The  experimental  results  may  be 
summarized  in  two  statements :  there  is  for  each  warm-blooded  animal 
a  temperature  at  which  the  ingestion  of  food  equal  only  to  the  starva- 
tion catabolism  will  result  in  an  increased  production  of  heat;  when 
the  external  temperature  is  lowered,  the  amount  of  food  necessary 
to  make  evident  such  increase  of  heat  production  is  greatly  in  excess 
of  the  starvation  requirement.  In  other  words,  there  is  an  excess  of 
heat  production  over  that  of  the  fasting  organism  associated  with  the 
ingestion  of  food  under  all  circumstances;  but  whether  this  excess 
of  heat  production  becomes  evident  depends,  apart  from  muscular 
work,  upon  the  external  temperature.  If  the  animal  be  at  work  or 
living  under  a  temperature  less  than  30°  C.  (for  the  dog,  this  probably 
varies  with  different  animals  depending  upon  their  coat),  the  extra 
heat  produced  on  ingestion  of  food  spares  heat  produced  through 
chemical  regulation  or  exertion,  and  the  curve  of  heat  production  does 
not  rise.  But  if  the  animal  be  resting  or  the  external  temperature  be 
above  30°  C,  the  curve  of  heat  production  rises  following  the  inges- 
tion of  food,  and  this  extra  heat  is  a  total  loss  to  the  economy.  The 
mechanism  of  chemical  regulation  of  body  temperature  is  not  opera- 
tive above  30°  C;  below  this  point  it  is  operative,  and  the  extra  heat 
produced  following  the  ingestion  of  food  is  of  use  to  the  body,  since 
other  combustion  is  spared  to  the  extent  of  the  extra  heat  thus  set 
free.  The  heat  production  of  an  animal  doing  constant  work  at  a 
constant  temperature  is  uniform  and  not  affected  by  the  ingestion 
of  food;  under  these  circumstances,  therefore,  the  extra  heat  evolved 
following  the  ingestion  of  food  is  made  use  of  for  support  of  work. 

Heat  Production. — Two  sets  of  experiments  make  the  relations  clear. 
Under  a  constant  temperature  of  30°  C.  a  resting  dog  is  found  to  have 
a  total  heat  output  of  750  Calories.  If  meat  to  the  value  of  750  Calories 
be  administered  in  a  day  under  comparable  conditions,  it  will  be  found 
that  the  heat  output  is  raised  to  possibly  1000  Calories.  If  the  input 
of  meat  be  raised  to  1000  Calories,  the  animal  will  be  in  caloric  equilib- 
rium. If  the  same  fasting  dog  be  made  to  do  a  certain  amount  of  work 
on  an  ergometer  (22,000  kgm.),  so  that  the  heat  output  is  raised  to  1000 
Calories,  it  will  be  found  that  the  ingestion  of  the  same  ration  that  in  the 
resting  dog  raised  the  heat  output  to  1000  Calories  will  do  just  the  same 
with  the  dog  at  the  stated  words.  In  other  work,  working  or  resting  on 
a  protein  diet  worth  750  Calories,  the  heat  output  of  the  dog  will  be  1000 
Calories;  the  heat  that  is  lost  at  rest  is  convertible  into  work  under 
controlled  and  comparable  conditions.      The  ingestion  of  the  amount 


THE  SPECIFIC  DYNAMIC  ACTION  OF  FOODSTUFFS        471 

of  protein  corresponding  to  750  Calories  will  not  place  the  dog  in  a 
carloric  equilibrium;  nor  need  the  ingestion  of  the  amount  of  protein 
corresponding  to  the  nitrogenous  elimination  of  the  fasting  animal 
place  the  animal  in  nitrogenous  equilibrium.  When,  however,  enough 
protein  is  administered  to  the  dog  to  attain  nitrogenous  equilibrium, 
it  will  be  found  that  the  output  of  heat  is  in  excess  of  the  heat  produc- 
tion of  the  animal  fasting  at  the  stated  temperature.  The  data  with 
low  ingestions  of  protein  suggest  the  idea  that  the  body  is  more  efficient 
in  the  catabolism  of  its  own  protein  than  in  the  utilization  of  protein 
of  the  diet.  It  is  possible,  however,  to  show  by  exaggeration  of  the 
catabolism  of  the  animal's  own  protein,  a  similar  excess  of  heat  produc- 
tion. This  may  be  noted  in  a  comparison  of  the  nitrogenous  output 
with  the  heat  output  in  dogs  suffering  from  phloridzin  poisoning;  for 
every  unit  of  excessive  protein  catabolized,  an  excess  of  heat  produc- 
tion of  about  30  per  cent,  will  be  recorded. 

When  protein  is  administered  in  excess  of  the  caloric  requirements 
of  the  fasting  body,  with  increasing  ingestions  the  excess  of  heat  produc- 
tion tends  to  become  augmented.  If  a  dog,  for  example,  has  a  require- 
ment of  1000  Calories,  and  is  given  meat  worth  1500  Calories,  the  heat 
output  will  be  about  1200  Calories.  If  the  ingestion  of  meat  be  raised 
to  2000  Calories,  the  heat  output  will  be  some  1400  Calories.  In  a  general 
sense,  therefore,  the  larger  the  protein  input  in  excess  of  the  caloric 
requirements  of  the  body,  the  greater  will  be  the  loss. 

The  relations  are  also  made  clear  by  the  results  of  the  administra- 
tion of  different  known  amounts  of  protein  to  dogs  of  known  weight 
and  caloric  output  at  fixed  external  temperature.  The  following 
tables,  taken  from  the  studies  of  Rubner,  make  the  facts  clear: 

Calories  per  Kilo  Body  Weight  per  Day 


External 
temperature. 

Fasting 
output. 

Diet  of  100  grams 
meat,  24  Cal.  per 
kilo. 

Diet  of  200  grams 

meat,  48  Cal.  per 

kilo. 

Diet  of  320  grams 

meat,  81  Cal., 

per  kilo. 

7°C. 
15°  C. 

20°  C. 
25°  C. 
30°  C. 

86.4 
63.0 
55.9 
54.2 
56.2 

55*9 
55.5 
55.6 

77.7 

57^9 
64.9 
63.4 

87.9 
86.6 
76.3 

83^6 

The  lessened  requirements  with  rising  external  temperature  are  clearly 
shown.  Each  input  corresponds  to  a  fairly  constant  output  at  the 
different  temperatures.  When  these  are  contrasted  with  the  figures 
for  fasting,  the  relation  becomes  clear.  Only  the  heavy  input  could 
cover  the  needs  at  the  lowest  temperature;  with  each  rise  in  external 
temperature  to  25°,  the  loss  becomes  more  pronounced.  The  ration 
of  200  grams  could  not  cover  the  needs  at  7°,  but  did  cover  the  needs 


472 


METABOLISM  CONSIDERED  AS  A  WHOLE 


at  20°  (probably  also  at  15°);  at  25°  and  30°  there  is  a  heat  loss  of  20 
per  cent.  The  lowest  ration  could  not  cover  the  needs  at  7°,  certainly 
not  also  at  15°;  but  from  that  time  on  did  so  exactly.  The  increase  in 
protein  input  from  100  to  320  grams  of  meat  at  the  constant  tempera- 
ture of  25°  to  30°,  raised  the  heat  production  nearly  30  Cal.  per  kilo 
per  day  over  the  figure  for  the  same  dog  at  fasting  or  at  input  of  100 
grams. 


Calories  per  Kilo  Body  Weight  per 

Day 

External 
temperature. 

Fasting. 

Diet  275  grams  meat 
=86.9  Cal.  per  kilo. 

Diet  550  grams  meat  = 
173.6  Cal.,  per  kilo. 

4.8°  C. 
14.6°  C. 
22.1° C. 
30.7°  C. 

121.3 

100.9 

70.7 

62.0 

121.9  (-) 
96.1 

83,7  (18%) 
81.7  (31%) 

133.5  (   9.0%) 

110.9  (10.0%) 
101.0  (42.9%) 
117.2  (89.0%) 

Apart  from  one  aberrant  result  and  with  some  fluctuations  in  the 
lower  values,  the  same  relations  are  here  indicated. 

This  result  we  ascribe  to  the  specific  dynamic  action  of  the  protein. 
Fat  and  carbohydrate  have  also  a  specific  dynamic  action,  but  as  it 
is  very  much  less  than  that  of  protein,  the  action  of  the  latter  has  been 
chosen  as  illustration. 

These  facts  possess  a  peculiar  and  particular  interest  to  the  student 
of  nutrition  of  the  human  body.  Under  modern  conditions  of  life, 
man  is  practically  independent  of  the  chemical  regulation  of  body 
temperature.  The  heating  of  dwellings  and  the  use  of  clothing  modified 
to  meet  the  particular  conditions  of  external  temperature  make  us 
relatively  independent  of  chemical  regulation.  The  temperature  of  the 
skin  of  the  clothed  portions  of  the  body,  under  the  usual  conditions  of 
indoor  life,  is  about  33°  C.  Metabolism  in  a  bath  at  33°  C.  has  been 
shown  to  be  identical  with  the  metabolism  of  the  dressed  individual 
at  room  temperature.  Even  out  of  doors  it  is  doubtful  if  the  tempera- 
ture of  the  clothed  skin  falls  below  30°  C.  Under  conditions  of  pro- 
longed exposure  to  extreme  temperatures,  even  despite  heavy  clothing, 
it  is  however  certain  that  the  temperature  of  the  skin  may  fall  below 
this  figure;  and  under  these  circumstances  the  mechanism  for  the 
chemical  regulation  of  the  body  temperature  becomes  operative.  But 
under  usual  conditions  of  life,  the  extra  heat  production  expressive  of  the 
specific  dynamic  action  of  the  foodstuffs  must  be  apparent  in  the  resting 
state,  and  must  be  taken  into  account  in  our  conception  of  metabolism. 

Careful  experimentation  on  the  dog,  checked  up  with  data  derived 
from  diet  experiments  on  human  beings,  has  made  it  possible  for  us 
to  estimate  closely  the  increments  of  heat  that  are  herein  concerned. 
There  are  doubtless  individual  variations,  but  the  figures  tend  to  hold 


THE  SPECIFIC  DYNAMIC  ACTION  OF  FOODSTUFFS        473 

for  usual  normal  conditions.  The  figures  are  known  most  accurately 
for  ingestions  that  correspond  approximately  with  the  basal  require- 
ments noted  during  fasting.  For  protein  in  particular,  with  ingestions 
greatly  in  excess  of  the  figure  for  the  starvation  output  in  calories, 
more  extra  heat  is  probably  set  free.  For  protein  it  is  safe  to  place 
the  heat  eliminated  as  the  result  of  the  specific  dynamic  action  at 
from  25  to  35  per  cent,  of  the  intake,  30  per  cent,  being  a  fair  average; 
for  fat  the  figure  is  about  12  per  cent.;  for  carbohydrate  much  less, 
about  6  per  cent.  In  other  words,  if  a  resting  body  at  a  constant 
temperature  of  33°  C,  set  free  during  fasting  2900  Calories  of  heat, 
when  fed  under  identical  conditions  100  grams  of  protein,  100  grams 
of  fat,  and  400  grams  of  carbohydrate  the  heat  production  would  be 
about  3200  Calories,  though  the  actual  heat  value  of  the  intake  was 
only  2900.  To  meet  the  difference,  place  the  body  in  caloric  equilibrium 
and  maintain  the  same  ratios  between  the  three  foodstuffs,  the  diet 
would  need  to  be  increased  to  about  140  grams  protein,  114  grams 
fat,  and  425  grams  of  carbohydrate. 

When  these  considerations  are  applied  to  mixed  diets  the  relations 
must  be  somewhat  modified.  The  greater  the  relative  ration  of  protein, 
the  larger  would  be  the  specific  dynamic  action.  For  mixed  diets, 
from  10  to  15  per  cent,  more  calories  must  be  offered  than  the  body 
liberates  during  fasting.  It  is  possible  to  calculate  for  different  diets 
about  what  the  input  would  need  to  be.  Such  a  calculation  is  based 
on  the  assumption  that  the  specific  dynamic  action  is  proportional 
to  the  mass  of  protein  catabolized.  As  a  matter  of  fact,  with  large 
ingestions  of  protein  the  specific  action  seems  to  be  more  intense,  but 
the  difference  would  not  materially  affect  the  figures.  For  the  carbo- 
hydrates and  fats  the  contrary  is  true;  if  fed  in  excess  of  the  basal 
requirements  of  Calories,  the  specific  dynamic  action  recedes,  the  body 
tends  to  burn  of  carbon  administered  in  carbohydrates  and  fats  only 
what  is  needed  to  maintain  the  heat  requirement. 

Amounts  of  food  in  named  mixed  diets  necessary  to  maintain  Caloric 
equilibrium  in  an  individual  of  70  kilo  weight  and  fasting  resting 
requirement  of  2100  Calories  per  day. 

(In  each  line  the  bracketed  figures  represent  the  amounts  that  would 
yield  the  calories  of  the  basal  requirements;  below  are  the  actual 
amounts  that  would  need  to  be  ingested  to  keep  the  body  in  caloric 
equilibrium.  The  caloric  values  have  been  calculated  as  rounded 
figures;  proteins,  4;  carbohydrate,  4;  and  fat,  9.  All  the  figures  are 
given  rounded.  In  the  last  two  diets,  free  of  protein,  the  production  of 
heat  would  be  augmented  over  the  amounts  given  by  the  catabolism  of 
the  endogenous  protein,  about  150  Calories  in  the  first  instance  and 
probably  250  Calories  in  the  second  instance.  These  figures  have  not 
been  included  in  the  totals.) 


474  METABOLISM  CONSIDERED  AS  A   WHOLE 


Protein 

Carbohydrate 

Fat 

Caloriea 

(525) 
700 

(0) 
0 

(0) 
0 

(2100) 
2800 

(200) 
280 

(165) 
175 

(70) 
80 

(2100) 
2550 

(150) 
210 

(250) 
265 

(55) 
65 

(2100) 
2500 

(150) 
210 

(125) 
135 

(110) 
125 

(2100) 
2600 

(125) 
175 

(250) 
265 

(65) 
75 

(2100) 
2425 

(125) 
175 

(150) 
160 

(110) 
125 

(2100) 
2475 

(100) 
140 

(300) 
320 

(55) 
65 

(2100) 
2400 

(100) 
140 

(200) 
215 

(100) 
115 

(2100) 
2450 

(75) 
105 

(300) 
320 

(65) 
75 

(2100) 
2375 

(75) 
105 

(225) 
250 

(100) 
115 

(2100) 
2450 

(60) 
85 

(350) 
370 

(50) 
57 

(2100) 
2340 

(60) 
85 

(240) 
255 

(100) 
115 

(2100) 
2375 

(40) 
55 

(375) 
400 

(50) 
57 

(2100) 
2325 

(0) 
0 

(525) 
555 

(0) 
0 

(2100) 
2225 

(0) 
0 

(0) 
0 

(235) 
270 

(2100) 
2425 

Under  the  discussion  of  the  processes  of  digestion  it  was  pointed  out 
that  in  the  acts  of  digestion  work  is  performed.  The  nitrogenous 
metabolism,  measured  by  the  output  of  nitrogen  in  the  urine,  is  not 
increased  by  mock  feeding,  though  this  is  associated  with  active  secre- 
tion of  alimentary  juices.  A  certain  heat  production  is  found  to  be 
associated  with  this  secretion.  It  is  clear  that  the  specific  dynamic 
action  of  the  foodstuffs  as  a  whole,  cannot  be  related  to  this  work. 
This  is  made  definite  by  the  fact  that  the  amino-acids  derived  from  a 
unit  of  casein  display  the  same  specific  dynamic  action  when  admin- 
istered to  a  dog  as  the  casein  from  which  they  were  obtained;  and  by 
the  further  fact  that  when  the  phloridzinized  dog  burns  his  body 
protein,  the  same  excess  of  heat  production  is  to  be  noted.  For  protein, 
therefore,  it  is  certain  that  the  specific  dynamic  action  is  not  related 


THE  SPECIFIC  DYNAMIC  ACTION  OF  FOODSTUFFS        475 

to  the  processes  of  digestion,  but  lies  within  the  catabolism.  For  the 
carbohydrates  and  fats,  the  interpretation  is  probably  different.  On 
the  assumption  that  the  fats  are  resynthesized  in  the  intestinal  wall, 
the  chemical  reaction  of  the  total  fat  digestion  is  isothermic.  When 
starches  and  disaccharids  are  split  into  hexose,  from  3  to  5  per  cent, 
of  the  contained  heat  is  set  free.  In  the  case  of  protein,  parenteral  intro- 
duction is  followed  by  increase  in  heat  production.  The  parenteral 
introduction  of  glucose  or  fat  is  not  followed  by  a  rise  in  the  produc- 
tion of  heat.  Indeed,  the  ingestion  of  75  grams  of  glucose  by  a  fasting 
subject  is  not  followed  by  any  rise  in  the  production  of  carbon  dioxid, 
the  glucose  evidently  being  simply  stored  as  glycogen.  And  when 
the  body  is  in  caloric  equilibrium,  the  further  ingestion  of  sugar  and 
fat  is  associated  with  but  very  little  specific  dynamic  action.  For 
the  sugars  this  could  be  explained  by  their  conversion  into  glycogen. 
All  in  all,  it  seems  very  likely  that  for  fat  and  carbohydrate  the 
specific  dynamic  action  is  largely  related  to  the  work  of  digestion  and 
assimilation,  though  for  the  fats  the  details  are  not  clear. 

Since  it  cannot  be  assumed  that  the  specific  dynamic  action  of 
protein  is  associated  with  the  acts  of  digestion  and  assimilation,  could 
it  be  related  to  the  elimination  of  the  end  products  of  nitrogenous 
metabolism?  The  elimination  of  urea  costs  work  and  heat  is  set  free; 
this  can  be  shown  experimentally.  But  the  amount  of  heat  involved 
is  entirely  too  small  to  explain  the  facts. 

Another  possibility  lies  in  the  combustion  of  superfluous  amino- 
acids,  after  the  postulated  conversion  of  diet  protein  into  the  blood 
proteins.  If  this,  in  part,  could  be  invoked  to  explain  the  specific 
dynamic  action  of  protein,  it  ought  to  be  greatest  in  the  case  of  the 
ingestion  of  proteins  whose  amino-acid  composition  is  farthest  from 
that  of  the  blood  protein,  for  example,  gliadin;  it  ought  to  be  lowest 
after  the  ingestion  of  the  blood  serum  of  the  same  species.  This  sugges- 
tion is  in  harmony  with  the  increase  in  heat  production  observed  when 
the  starving  animal  is  subjected  to  phloridzin  poisoning;  the  animal 
must  convert  indifferent  protein  of  the  connective  tissues  and  after 
that  muscle  protein  into  blood  and  cell  protein,  and  superfluous 
amino-acids  would  be  here  set  free. 

However  stated,  it  is  certain  that  the  phenomenon  is  not  associated 
with  the  anabolism  of  cellular  protein  directly,  but  is  a  waste  that 
attends  this  process  and  also  a  waste  that  attends  the  catabolism  of 
exogenous  protein.  The  total  potential  energy  of  protein  is  not  avail- 
able for  cellular  or  metabolic  needs.  To  say  that  it  is  the  heat  of 
chemical  reaction,  explains  nothing.  There  is  a  difference  between 
the  heat  value  of  the  metabolizable  products  that  the  protein  presents 
to  the  cells  and  the  heat  value  in  the  protein  potentially;  this  appears 
as  free  heat  and  though  it  can  be  utilized  for  work  and  to  spare 
combustions  through  chemical  regulation  of  temperature,  it  cannot  be 
utilized  by  the  cells  for  anabolic  purposes.  The  total  heat  value  of  a 
gram  of  protein  may  be  set  at  5.7  Calories.    Of  this  about  1.5  Calories 


476  METABOLISM  CONSIDERED  AS  A   WHOLE 

reappear  in  the  end  products  in  the  urine.  Of  the  4.2  Calories  that 
are  then  available  in  the  body,  about  2  to  2.5  Calories  remain  stored 
in  glucose,  leaving  about  2  Calories  or  a  little  more  still  unaccounted 
for.  The  fatty  acids  that  are  not  convertible  into  glucose  are  burned, 
and  these  yield  probably  not  over  1  Calorie,  calculating  on  the  basis  of 
the  carbon  that  remains  after  the  extent  of  glucose  formation  has  been 
determined.  The  balance  remains  unaccounted  for  (for  metabolic 
needs),  and  corresponds  to  the  heat  set  free  through  the  specific 
dynamic  action  of  the  protein.  Contemplating  the  specific  dynamic 
action  of  protein  from  this  point  of  view,  the  moment  of  loss  would 
seem  to  lie  in  the  conversion  of  the  amino-acids  into  glucose,  i.  e.,  the 
glucose  formed  from  a  unit  of  amino-acid  contains  less  heat  than  did 
the  substrate,  and  this  heat  set  free  is  a  loss  to  the  metabolism  and 
constitutes  the  heat  of  the  specific  dynamic  action  of  protein.  This 
hypothesis  has  not  been  tested  experimentally. 

The  phenomenon  is  of  little  practical  importance  in  health,  but 
constitutes  a  misfortune  to  the  diabetic.  Probably  the  sensation  of 
warmth  that  follows  a  meal  rich  in  protein  is  due  to  this  specific  dynamic 
action  of  protein;  and  this  suggests  that  the  protein  ration  be  lower 
in  summer  than  in  winter,  and  should  be  as  low  in  fevers  as  may  be 
consistent  with  the  maintenance  of  nitrogenous  equilibrium.  For  the 
diabetic  the  loss  of  heat  is  a  real  misfortune;  because  with  the  inability 
to  burn  sugar,  the  energy  available  to  the  cells  of  the  diabetic  may 
be  reduced  to  1  Calorie  per  gram  of  protein. 

THE  RECIPROCAL  RELATIONS  OF  PROTEIN,  CARBOHYDRATE, 

AND    FAT 

The  Relations  of  the  Non-nitrogenous  Derivatives  of  Protein. — The 
disposition  of  the  nitrogenous  derivatives  of  the  protein  molecule 
was  stated  under  Protein  Metabolism.  About  the  fate  of  the  non- 
nitrogenous  fraction  has  centred  in  the  past  the  most  intense  interest, 
and  over  this  fraction  have  been  waged  some  of  the  most  determined 
controversies  in  the  history  of  physiology.  With  the  demonstration 
of  the  origination  of  glucose  from  the  amino-acids  derived  from  the 
catabolism  of  protein,  the  meaning  of  the  carbon  retentions  noted 
in  animals  on  pure  protein  diets  became  unquestioned.  As  stated 
elsewhere,  the  exact  amount  of  glucose  that  the  body  derives  from 
a  unit  of  protein  is  not  known;  and  probably  it  varies  with  different 
proteins.  It  will  be  safe  to  assume  with  mixed  diets  that  a  gram  of 
protein  will  yield  0.5  or  possibly  0.6  gram  of  sugar.  Once  this  sugar 
is  formed,  it  shares,  of  course,  all  the  obligations  and  prerogatives  of 
glucose  within  the  animal  economy.  And  since  fat  is  formed  from 
sugar,  in  this  indirect  way  fat  is,  of  course,  formed  from  protein.  But 
so  far  as  we  know,  fat  is  only  formed  from  protein  within  the  general 
metabolism;  glucose  is  first  formed  from  the  amino-acids  and  from  this 
sugar,  as  from  all  sugar,  fat  may  be  formed.    When  with  an  excess 


THE  RELATIONS  OF  PROTEIN,  CARBOHYDRATE,  AND  FAT     477 

of  protein  intake  glucose  is  being  stored  from  protein,  1  gram  of 
protein  will  yield  about  a  fourth  gram  of  fat.  To  obtain  this  fat, 
however,  the  body  must  catabolize  the  protein  and  eliminate  the 
nitrogenous  end  products,  so  that  it  is  a  very  wasteful  method  of  lay- 
ing on  fat,  5.7  Calories  protein  input  yielding  2.3  Calories  stored  fat. 

When  the  body  is  fasting,  the  concentration  of  glucose  in  the  blood 
remains  normal,  even  when  it  is  certain  that  the  glycogenous  deposits 
are  quite  depleted.  This  concentration  of  sugar  in  the  blood  under 
these  circumstances  is  maintained  by  glucose  derived  from  the  catab- 
olism  of  the  body  protein. 

When  protein  is  being  catabolized  in  excess,  it  seems  in  some  way 
to  entrain  the  combustions  of  sugar  and  fat.  Sugar  and  fat  have  a 
low  specific  dynamic  action.  It  seems,  however,  that  when  they  are 
ingested  with  large  amounts  of  protein,  this  action  is  more  pronounced ; 
the  excess  of  heat  production  inclines  to  be  more  than  would  be  observed 
for  the  fat  and  sugar  and  protein  tested  separately.  In  other  words, 
the  exaggeration  of  the  protein  catabolism  tends  to  exaggerate  the 
combustions  of  fat  and  sugar. 

Influence  of  Metabolism  of  Fat  and  Carbohydrate  upon  Each  Other. — 
Disregarding  the  differences  in  the  specific  dynamic  actions  of  fat 
and  carbohydrate,  these  two  are  isodynamically  equivalent,  i.  e.,  they 
are  able  to  replace  each  other  as  sources  of  energy  and  heat  in  the 
proportions  of  their  caloric  values.  The  ingestion  of  fat  does  not 
materially  modify  the  progress  of  the  metabolism  of  carbohydrate. 
But  the  ingestion  of  carbohydrate  does  modify  the  metabolism  of 
fat.  The  body  burns  carbohydrate  by  preference.  If  to  a  body  being 
warmed  by  the  combustion  of  fat,  carbohydrate  be  administered,  the 
combustion  of  fat  will  be  lowered  or  cease,  and  be  replaced  by  the  burn- 
ing of  glucose;  and  the  respiratory  quotient  will  indicate  the  change. 
When  to  a  fasting  body  (being  warmed  by  the  combustion  of  fat)  a 
goodly  ration  of  sugar  is  administered,  the  carbon  dioxid  elimination 
rises  from  about  22  to  30  grams  per  hour.  This  is  due  to  the  combus- 
tion of  glucose  instead  of  fat,  there  is  more  carbon  dioxid  produced 
for  the  same  output  of  heat.  Certain  quantitative  conditions  must, 
however,  be  present.  If  the  man  has  fasted  long,  the  rise  in  carbon 
dioxid  does  not  occur;  instead  the  body  retains  the  sugar  and  continues 
to  burn  the  fat.  It  was  elsewhere  explained  with  what  tenacity  the 
body  attempts  to  maintain  a  certain  stage  of  storage  of  glycogen; 
if  this  has  been  depleted  by  starvation,  the  administration  of  sugar 
is  utilized  by  the  body  for  the  repletion  of  this  glycogen.  But  when 
the  reserves  of  glycogen  are  relatively  restored,  even  though  the  sub- 
ject be  burning  largely  fat,  the  ingestion  of  sugar  will  swing  that  body 
from  the  combustion  of  fat  to  that  of  sugar,  with  the  consequent 
increase  in  the  output  of  carbon  dioxid.  When  carbohydrates  are 
ingested  in  great  excess  and  active  conversion  of  sugar  into  fat  is  going 
on,  the  respiratory  quotient  may  be  higher  than  1,  since  the  conversion 
of  the  carbon  and  hydrogen  of  glucose  into  fat  sets  free  oxygen  that 


478  METABOLISM  CONSIDERED  AS  A   WHOLE 

is  used  in  the  combustions  of  the  body  to  the  exclusion  of  atmospheric 
oxygen.  The  test  is  not  to  be  made  on  all  animals,  since  many  "animals 
will  not  deposit  fat  with  such  rapidity.  Respiratory  quotients  of 
over  1.3  have  been  obtained  in  connection  with  forced  feeding  of  carbo- 
hydrate in  the  goose  and  marmot. 

The  statement  that  sugar  and  fat  are  isodynamic  in  heat  production 
under  comparable  conditions  has  normally  no  exceptions.  But  it  is 
a  different  thing  to  state  that  in  any  individual,  carbohydrate  and 
fat  may  replace  each  other  in  the  diet  in  the  relation  of  the  caloric 
coefficients.  The  digestion  may  introduce  a  new  factor.  A  body  may 
require  600  grams  of  carbohydrate  (plus  the  standard  ration  of  protein) 
to  maintain  caloric  equilibrium;  250  grams  of  fat  would  supply  the 
same  heat.  But  the  body  may  not  be  able  to  digest  the  250  grams 
of  fat.  Occasionally  one  sees  individuals  whose  powers  of  digestion 
of  fat  are  very  limited;  one  meets  also  with  subjects  whose  powers  of 
digestion  of  carbohydrates  are  limited.  It  is  not  the  ingestion  of 
carbohydrate  and  fat  in  the  isodynamic  ratio,  it  is  the  assimilation  of 
carbohydrate  and  fat  in  the  isodynamic  ratio  that  constitutes  the 
dynamic  principle — a  point  to  be  borne  in  mind  with  the  sick. 

Comparable  as  fat  and  carbohydrate  are  to  each  other  as  mere 
fuels  under  controlled  conditions,  when  tested  in  relation  to  the  protein 
metabolism  they  present  widely  varying  properties.  Glycogen  and 
fat  were  defined  as  the  proximate  and  ultimate  states  of  storage  of 
glucose.  In  their  relations  to  the  protein  metabolism,  sugar  and  fat 
are  respectively  proximate  and  ultimate  in  availability. 

The  Saving  Power  for  Protein. — Both  fat  and  carbohydrate  have 
the  power  of  sparing  protein.  But  this  power  is  low  in  the  case  of 
fat  and  very  high  in  the  case  of  carbohydrate.  Let  the  nitrogen  output 
of  a  fasting  object  be  determined  and  enough  carbohydrate  and  fat 
be  administered  in  successive  tests  to  cover  the  caloric  needs  of  the 
body.  It  will  be  found  that  on  such  administration  of  carbohydrate 
the  nitrogen  output  will  fall  to  a  third  of  the  fasting  figure.  If  the 
individual  be  in  good  flesh,  the  administration  of  fat  will  result  in 
little  reduction  in  the  nitrogen  output.  If  the  subject  be  emaciated, 
however,  the  administration  of  fat  will  result  in  a  reduction  in  the 
nitrogen  output,  though  not  comparable  to  that  achieved  by  the 
carbohydrates.  Not  only  does  carbohydrate  actually  reduce  the 
nitrogen  metabolism  much  lower  than  fat,  it  will  do  this  in  amounts 
that  do  not  cover  the  caloric  needs  of  the  body,  the  balance  of  the 
heat  being  obviously  derived  from  the  fats  of  the  body.  Under  com- 
parable conditions,  if  feeding  with  just  enough  protein  and  carbo- 
hydrate to  cover  the  requirements  results  in  a  nitrogenous  equilibrium 
at  about  the  fasting  level,  the  substitution  of  fat  for  the  carbohydrate 
will  raise  the  nitrogen  elimination  about  one-half.  When  a  low  nitrogen 
equilibrium  is  maintained  by  a  ration  of  carbohydrate  just  sufficient 
to  cover  the  caloric  needs  of  the  body,  a  third  of  the  carbohydrate 
may  be  replaced  by  fat  without  disturbing  the  balance  of  nitrogen. 


THE   RELATIONS  OF  PROTEIN,  CARBOHYDRATE,  AND  FAT     479 

The  sparing  power  of  carbohydrate  and  fat  for  protein  may  be 
determined  in  another  way.  Under  certain  circumstances  the  body 
retains  nitrogen.  When  this  is  true,  such  retention  is  favored  by  carbo- 
hydrate much  more  than  by  fat.  One  reason  for  the  difference  lies 
obviously  in  the  fact  that  the  body  contains  little  carbohydrate  and 
much  fat.  The  further  addition  of  fat  could  not,  therefore,  be  expected 
to  have  much  metabolic  influence.  The  mechanism  of  the  protein 
metabolism  (and  of  the  fat  metabolism  as  well),  is  singularly  dependent 
upon  the  presence  of  glucose  and  glycogen.  If  these  be  absent  or 
seriously  reduced  (and  this  is  easily  accomplished),  their  administration 
greatly  influences  transformations.  The  marked  difference  in  the  sav- 
ing power  of  fat  and  carbohydrate  for  protein  makes  it  impossible  to 
explain  this  saving  as  the  mere  restriction  of  the  protein  catabolism 
to  the  endogenous,  cellular  activity,  to  the  exclusion  of  dynamogenetic 
utilization.  And  even  within  the  realm  of  purely  endogenous,  cellular 
protein  metabolism,  carbohydrate  spares  and  enables  the  body  to 
maintain  a  nitrogenous  equilibrium  on  the  lowest  possible  level,  far 
below  the  level  reached  with  fat  ingestions  more  than  covering  the 
caloric  needs  of  the  body. 

The  striking  influence  of  carbohydrate  utilization  on  the  catabolism 
of  protein  is  best  shown  in  deprivation  experiments.  A  fasting  man 
will  eliminate,  after  the  first  few  days  when  the  more  or  less  variable 
stock  of  surplus  protein  is  exhausted,  from  10  to  15  grams  of  nitrogen 
per  day.  This  elimination  slowly  falls  with  the  continuance  of  fasting. 
If  now  carbohydrates  be  ingested  in  amount  to  insure  caloric  equilib- 
rium, the  nitrogenous  elimination  will  fall  directly  to  4  or  5  grams 
and  remain  there  or  fall  indeed  still  farther.  The  substitution  of  fat 
for  carbohydrate  will  be  followed  by  a  rebound  of  the  nitrogen  almost 
to  the  earlier  figure  of  the  fasting  period.  By  prolonged  deprivation 
of  protein  with  rich  feeding  of  carbohydrate,  the  nitrogenous  output 
can  be  reduced  to  a  most  surprising  minimum,  to  scarcely  more  than 
2  grams  per  day.  In  some  recent  work  on  this  subject  done  on  swine, 
in  which  it  was  found  that  the  basal  protein  catabolism  was  not  reached 
in  less  than  sixteen  days,  the  nitrogen  output  fell  to  amounts  as  low 
as  1  gram  per  day  for  young  pigs  of  20  kilos  weight.  In  other  words, 
the  administration  of  carbohydrate  .to  the  starving  body  so  spares 
protein  as  to  cut  the  loss  of  nitrogen  down  to  a  third  or  even  a  fourth. 
The  body  of  the  subject  in  starvation  has  an  abundance  of  fat;  the 
dynamogenetic  combustion  of  protein  is  not  obligatory  by  reason  of 
absence  of  fat;  but  protein  is  catabolized  instead  of  body  fat  to  the 
extent  of  two-thirds  of  the  protein  dissimilated.  Fat  is,  of  course, 
burned;  the  heat  production  does  not  begin  to  be  covered  by  the  catab- 
olism of  protein,  it  is  indeed  covered  largely  by  the  burning  of  fat. 
But  if  the  body  could  contain  stores  of  carbohydrate  as  it  does  stores 
of  fat,  we  would  observe  the  nitrogen  output  at  the  low  figure  that 
is  to  be  seen  in  protein  fasting  with  carbohydrate  input.  This  state 
of  affairs  constitutes  one  of  the  strongest  arguments  against  the 
hypothesis  of  the  conversion  of  fat  into  sugar. 


480  METABOLISM  CONSIDERED  AS  A   WHOLE 

With  the  aid  of  carbohydrates  the  body  may  be  kept  in  nitrogenous 
equilibrium  with  a  total  input  below  the  amount  necessary  to  attain 
caloric  equilibrium.  Thus  a  body  may  be  kept  in  nitrogen  balance 
at,  let  us  say,  7  grams,  on  a  caloric  input  of  2000  Calories,  with  a 
heat  production  of  2500  Calories.  Carbohydrate  alone  will  do  this,  the 
substitution  of  fat  for  a  large  fraction  of  the  carbohydrate  results  in 
deficit  of  nitrogen  through  exaggeration  of  protein  catabolism. 

With  the  aid  of  carbohydrate  the  excessive  protein  catabolism  that 
occurs  in  the  course  of  prolonged  febrile  infections  may  be  reduced  or 
indeed  obviated.  In  typhoid  fever,  for  example,  by  the  ingestion  of 
increased  amounts  of  sugar,  the  total  loss  of  nitrogen  that  is  usually 
to  be  recorded  for  the  period  of  sickness  may  be  greatly  minimized, 
perhaps  obviated.  In  other  words,  carbohydrate  spares  pathological 
as  well  as  normal  protein  catabolism. 

To  a  certain  extent  carbohydrate  favors  the  storage  of  protein  with 
ingestions  above  the  nitrogenous  requirements.  This  is  usually  not 
marked  in  adult  life.  The  idea  that  carbohydrate  spares  protein  all 
the  way  up  the  scale  of  increased  inputs  is  incorrect.  Usually  when 
we  reach  the  highest  level  of  normal  requirements,  the  ingestion  of 
even  large  amounts  of  carbohydrate  will  not  induce  the  body  to  spare 
the  nitrogen  by  retaining  the  protein.  In  growing  animals  it  probably 
does  tend  to  do  so,  and  there  is  experimental  evidence  that  growing 
animals  will  fleshen  better  on  a  fixed  input  of  protein  plus  carbohydrate 
than  on  the  same  protein  input  plus  the  isodynamic  amount  of  fat. 
For  a  short  time,  the  sudden  addition  or  withdrawal  of  carbohydrate 
will  have  its  effect  upon  the  nitrogenous  metabolism,  but  the  effect 
is  not  continuous.  One  of  the  most  careful  and  competent  students 
of  metabolism  has  recorded  the  following  personal  observation.  When 
on  a  mixed  diet,  with  a  nitrogen  input  of  20.5  grams  and  an  output 
of  19.8  grams  (a  balance),  the  withdrawal  of  350  grams  of  carbohydrate 
from  the  diet  resulted  in  an  increased  output  of  nitrogen,  on  the  second 
day  to  27  grams.  This  observation  induced  the  writer  to  reverse  the 
experiment.  To  a  diet  of  a  subject  in  nitrogenous  equilibrium  at  13 
grams  was  added  300  grams  of  carbohydrate;  the  nitrogen  of  the  urine 
fell  over  3  grams.  But  in  neither  of  these  tests  could  the  results  have 
persisted.  Both  probably  represent  local  disturbances  in  the  liver, 
rather  than  in  the  total  metabolism.  As  a  rule,  and  especially  for 
long  periods  of  time,  it  is  certain  that  carbohydrate  has  not  the  power 
to  save  protein  in  the  sense  of  storing  protein.  It  is  very  potent  in 
saving  protein  by  checking  waste  of  protein,  by  checking  the  burning  of 
protein  as  fuel,  and  by  aiding  the  cells  to  accomplish  their  endogenous 
metabolism  upon  the  most  economical  nitrogenous  basis. 

Another  concrete  illustration  of  the  saving  power  of  glucose  over 
the  protein  catabolism  is  afforded  in  recent  work  on  the  metabolism 
of  creatin-creatinin.  Creatin  is  one  of  the  most  important  bodies  in 
the  endogenous  catabolism;  it  is  set  free  in  the  muscle  cell  and  con- 
verted into  creatinin.  In  the  absence  of  carbohydrate,  this  conversion 
is  incomplete  and  creatin  appears  unaltered  in  the  urine. 


THE  RELATIONS  OF  PROTEIN,  CARBOHYDRATE,  AND  FAT     481 

There  is  a  relation  of  dependence  to  carbohydrate  exhibited  in  the 
combustion  of  fat,  in  that  while  the  combustion  of  the  molecule  of  fatty 
acid  is  accomplished  down  to  the  stage  of  butyric  acid,  below  this  point 
retardation  tends  to  occur  in  the  absence  of  utilization  of  carbohydrate. 
The  question  is  discussed  under  acidosis.  There  are  many  exceptions 
to  the  rule;  there  is  acidosis  with  normal  combustion  of  carbohydrate 
and,  on  the  other  hand,  sistence  of  carbohydrate  combustion  without 
the  development  of  acidosis.  But  physiologically  the  relationship  is 
very  impressive.  Whenever  the  body  is  thrown  from  the  combustion 
of  carbohydrate  to  the  combustion  of  fat — in  starvation  or  in  protein- 
fat  diet,  a  certain  degree  of  disturbance  is  to  be  noted  in  the  combus- 
tion of  fat,  revealed  by  acidosis  and  the  presence  of  ketonic  bodies 
in  the  urine. 

In  the  presence  of  severe  organic  disease  of  the  liver,  the  saving  power 
of  carbohydrate  for  protein  may  be  markedly  reduced.  Under  these 
circumstances  it  is  open  to  question  whether  some  of  the  high  nitrogen 
outputs  previously  noted  in  hepatic  diseases  were  not  instances  of 
relative  carbohydrate  starvation  with  consequent  increase  in  protein 
catabolism,  rather  than  direct  results  of  the  hepatic  conditions  on 
the  catabolism  of  protein. 

Adequate  explanation  of  the  nature  of  the  saving  power  for  protein 
exhibited  by  carbohydrate  is  not  at  hand.  It  is,  however,  apparent 
that  at  all  points  in  the  scale  the  cause  of  the  saving  power  is  not  the 
same.  There  is  the  saving  to  be  noted  with  moderate  ingestions  of 
protein,  as  when  on  an  input  of  7  grams  of  nitrogen,  a  nitrogenous 
balance  is  established  with  an  input  of  less  Calories  than  are  necessary 
to  cover  the  needs  of  the  body.  Let  us  say  the  heat  needs  of  the  body 
are  2100  Calories  and  1800  are  given  in  the  diet,  protein  corresponding 
to  7  grams  (150  Cal.)  plus  carbohydrate  (1650  Cal.).  The  missing 
300  Calories  are  obtained  by  combustion  of  body  fat.  Now  of  the 
carbohydrate  in  the  diet,  at  least  600  Calories  may  be  replaced  by  fat 
without  disturbing  the  balance  in  nitrogen.  Within  this  range  of 
1000  Calories  the  fat  and  carbohydrate  spare  protein  equally.  This 
saving  is  due  to  sparing  the  combustion  of  protein  for  dynamogenetic 
purposes.  The  other  1000  Calories  covered  by  carbohydrate  cannot, 
however,  be  replaced  by  fat.  Within  this  range  sugar  accomplishes 
something  that  fat  cannot  do.  In  part,  at  least,  an  explanation  for 
this  action  is  to  be  found  in  the  concentration  of  sugar  in  the  blood. 
In  complete  starvation  the  sugar  concentrations  is  preserved  in  the 
blood.  This  sugar  can  be  derived  from  but  one  source,  after  the  depots 
of  glycogen  have  been  depleted;  from  protein.  If  fat  be  given  instead 
of  carbohydrate — either  with  protein  ingestion  or  in  nitrogen  starva- 
tion— the  body  must  catabolize  protein  to  secure  sugar  to  maintain 
the  concentration  of  the  blood.  How  much  sugar  is  used  or  burned 
during  starvation  is  not  known;  but  much  is  not  burned,  as  indicated 
by  the  respiratory  quotient.  The  amount  of  sugar  that  corresponds 
to  1000  Calories  of  heat  is  250  grams,  and  no  such  amount  of  sugar 
31 


482  METABOLISM  CONSIDERED  AS  A   WHOLE 

as  this  can  be  needed  to  maintain  the  glucose  concentration  of  the 
blood  during  starvation.  To  yield  250  grams  of  sugar  500  grams  of 
protein  would  have  to  be  catabolized,  and  the  body  does  not  begin 
to  catabolize  this  much  in  complete  starvation.  Those  who  believe  in 
the  reutilization  of  nitrogen  in  amino-acids,  could  invoke  a  fraction 
of  this  sugar  to  that  end;  but  this  does  not  deserve  serious  considera- 
tion, in  the  opinion  of  the  writer.  For  the  present  we  can  simply  say 
that  the  processes  of  endogenous  protein  catabolism  are  more  effectively 
carried  on  in  a  body  supplied  with  carbohydrate  and  supported  by  it 
than  without  it.  This  is  not  an  explanation  at  all,  but  merely  a  state- 
ment of  fact.  It  is  true,  as  often  reiterated,  that  sugar  is  more  soluble 
and  more  readily  oxidizable  than  fat;  but  upon  these  properties  of 
sugar  in  the  body  the  peculiar  saving  power  of  glucose  cannot  depend. 
There  remains  finally,  the  ultimate  saving  in  protein  that  is  attained 
in  nitrogen  starvation  by  the  ingestion  of  amounts  of  carbohydrate 
in  excess  of  the  caloric  requirements.  Upon  this  low  plane  of  metab- 
olism, the  maintenance  of  the  sugar  concentration  in  the  blood  becomes 
a  factor  in  the  catabolism  of  protein.  Under  these  circumstances,  the 
operations  of  the  endogenous  cellular  catabolism  are  reduced  to  the 
most  minimal  plane,  less  than  half  that  on  which  nitrogenous  equilib- 
rium can  be  maintained  with  the  aid  of  carbohydrate.  Growth  cannot 
be  accomplished  under  such  conditions,  but  that  does  not  enter  into 
the  discussion  in  adults.  We  deal  here  apparently  with  an  expression 
of  the  peculiar  indispensability  of  glycogen  to  tissues.  In  the  discussion 
of  the  carbohydrate  metabolism  and  of  diabetes,  it  was  pointed  out 
with  what  marked  pertinacity  the  body  protects  its  store  of  glycogen, 
as  though  it  were  invaluable.  When  in  a  case  of  diabetes  the  reserves 
of  glycogen  in  the  tissues  are  greatly  depleted,  the  organism  is  apt 
to  collapse  like  the  One  Horse  Shay.  Conversely  to  this,  when  the 
maximum  storage  of  glycogen  is  attained  and  maintained  in  the  cells, 
their  endogenous  catabolism  of  protoplasm  is  accomplished  on  the  very 
minimal  basis.  In  some  way  glycogen  acts  as,  in  a  mechanical  sense, 
a  lubricant  is  related  to  the  wearing  parts  of  a  machine;  when  glycogen 
is  abundant,  the  wear-and-tear  is  slight;  when  it  is  deficient,  the  wear- 
and-tear  is  excessive.  The  situation  here  is  just  the  converse  presented 
in  the  relations  of  sugar  to  creatin  and  fat;  in  the  absence  of  sugar 
creatin  is  not  converted  into  creatinin,  and  fat  is  not  burned;  in  the 
absence  of  sugar  protein  is  inordinately  catabolized.  We  have  no 
explanation  of  this  in  chemical  terms.  It  is  possible  that  we  deal 
here  with  coupled  reactions,  the  relations  of  actor  and  inductor  being 
reversed  in  the  two  sets  of  conditions. 


INANITION 

It  is  the  usual  method  of  procedure  to  define  the  normal  state  and 
from  this  to  proceed  to  the  definition  of  abnormal  states.    And  from 


INANITION  483 

this  point  of  view  it  were  more  logical  to  discuss  the  normal  diet  before 
taking  up  the  subject  of  starvation.  But  so  much  has  developed  in 
the  study  of  different  starvations  that  is  directly  of  service  in  the 
discussion  of  the  normal  diet,  that  it  will  facilitate  progress  to  consider 
inanition  first.  Under  inanition  we  understand  the  withdrawal  of 
nutrients;  water  and  salts  are  not  withdrawn.  The  term  fasting  has 
the  same  meaning;  while  as  an  experimental  term  starvation  in  dogs 
is  usually  understood  to  mean  the  complete  withdrawal  of  ingesta. 
For  the  dog  water  is  not  required,  the  processes  of  catabolism  yield 
enough  water  to  dissolve  and  carry  out  the  salts  derived  from  metab- 
olism; and  the  dog  on  a  meat  diet  can  do  without  water  when  resting. 
But  this  is  only  the  case  in  such  animals  as  eliminate  little  or  no  water 
from  the  skin. 

Illustrative  as  fasting  experiments  have  been,  in  some  directions 
partial  hungers  have  given  more  crucial  information.  Such  are  protein 
hunger,  fat  hunger,  carbohydrate  hunger,  or  fasting  of  one  kind  com- 
bined with  variations  in  the  feeding  with  one  or  other  or  both  of  the 
two  permitted  foodstuffs.  If  the  metabolism  can  be  shifted  in  a  par- 
ticular direction  by  experimental  means,  as  in  diabetes,  phloridzin 
or  phosphorus  poisoning,  fasting  tests  may  be  made  to  yield  addi- 
tional information.  Our  data  are  not  confined  to  observations  on 
animals,  since  diet  fadists  and  professional  fasters  have  provided  well- 
utilized  opportunities  for  careful  chemical  study  of  inanition  in  man. 
And  finally,  there  is  pathological  material  from  which  valuable  informa- 
tion has  been  derived. 

Total  Fasting. — By  observations  on  professional  fasters  largely, 
the  length  of  time  the  body  can  maintain  itself  without  nutriment 
has  been  fairly  closely  determined.  Fifty  days  is  the  longest  fast  on 
record;  there  have  been  several  fasts  of  forty  and  thirty  days. 
Naturally,  the  length  of  time  the  body  can  conserve  itself  without 
food  is  inversely  proportional  to  the  fat  and  flesh  content  of  the  body 
at  the  beginning.  It  is  not  likely  that  under  the  best  conditions,  a 
man  could  fast  materially  over  fifty  days.  Dogs  often  die  within  a 
few  weeks,  yet  in  one  case  death  did  not  occur  before  the  ninety-eighth 
day.  Fasting  as  a  result  of  disease  is  scarcely  to  be  taken  as  typically 
illustrative  of  the  state,  since  the  organic  conditions  underlying  the 
inability  to  take  or  assimilate  food  (obstruction  of  esophagus  or  the 
pylorus,  etc.),  tend  to  make  the  conditions  of  nutrition  unfavorable. 
On  the  other  hand,  the  state  of  nutrition  in  certain  instances  of  carci- 
noma of  the  pylorus  is  largely  due  to  starvation;  and  the  formation 
of  a  gastroduodenal  anastomosis  has  at  least  the  effect  of  permitting 
the  subject  to  die  of  carcinoma  after  months,  instead  of  dying  from 
starvation  after  a  few  weeks. 

The  state  of  the  body  protein  has  a  marked  influence  on  the  metab- 
olism during  the  first  few  days  of  fasting,  especially  in  dogs,  though 
the  facts  would  doubtless  be  found  to  hold  for  man.  Under  ordinary 
conditions,  the  nitrogen  output  is  high  for  two  or  three  days,  then 


IM  METABOLISM  CONSIDERED  AS  A   WHOLE 

falls;  but  if  the  fasting  has  been  preceded  by  a  heavy  protein  input, 
this  stage  of  high  nitrogenous  elimination  will  last  for  two  or  three 
days  longer.  There  is  a  certain  degree  of  protein  storage  that  can 
be  accomplished,  and  the  nitrogenous  output  of  the  early  days  of 
fasting  is  related  to  this  variable.  Marked  also  is  the  influence  of 
stored  glycogen  on  the  course  of  metabolism  during  the  first  days  of 
inanition,  the  result  being  just  the  converse  of  the  effect  of  stored 
protein.  The  nitrogen  output  will  be  low  for  from  two  to  five  days, 
depending  on  the  amount  of  glycogen  stored;  then  it  will  rise  to  about 
the  same  figure  to  which  it  would  have  fallen  in  the  same  individual 
had  the  state  of  nutrition  been  stored  protein  instead  of  glycogen. 
Thus  the  daily  nitrogen  output  in  a  subject  well  stocked  with  glycogen 
may  be  8,  11,  12,  13,  14  grams;  while  in  fasting  following  forced  protein 
feeding  the  daily  output  of  nitrogen  would  be  18,  17,  15,  14,  13.  The 
respiratory  quotient  (about  0.7  in  established  starvation)  would  be 
higher  in  the  subject  with  much  glycogen.  The  figures  are,  of  course, 
arbitrary,  but  they  represent  the  general  course  of  the  nitrogenous 
elimination.    Nitrogen  is  lost  most  rapidly  in  thin  subjects. 

The  influence  of  stored  fat  is  twofold.  The  plane  of  the  nitrogenous 
output  is  inclined  to  be  lower  in  fat  individuals;  and  the  middle  period 
of  even  metabolism  that  is  to  be  observed  in  all  cases  of  inanition  is 
greatly  prolonged.  After  a  number  of  days,  the  body  seems  to  improve 
in  its  protein  metabolism  on  the  enforced  basis  of  fat  minus  carbo- 
hydrate, and  acidosis  may  not  be  at  all  pronounced.  This  favorable 
action  of  abundant  body  fat  on  the  course  of  inanition  is  especially 
well  illustrated  in  the  dog.  And  in  the  dog  is  recorded  the  longest 
survival  on  record  in  starvation,  one  hundred  and  seventeen  days. 

The  relation  of  the  catabolism  of  protein  to  the  total  heat  produc- 
tion is  relatively  constant  under  controlled  conditions,  after  the  stored 
protein  and  glycogen  have  been  exhausted.  During  the  intermediary 
stage  of  starvation,  the  catabolism  of  protein  yields  from  10  to  15 
per  cent,  of  the  total  heat  production;  both  fall,  but  the  reduction  in 
the  nitrogen  is  the  more  marked  and  its  relative  participation  in  the 
total  heat  production  is  lessened.  Thus  in  prolonged  fasting,  during 
and  after  the  third  week,  the  catabolism  of  protein  may  furnish  no 
more  than  5  per  cent,  of  the  total  heat  production. 

The  curve  of  total  heat  production  for  a  prolonged  fast  has  not  been 
determined,  though  by  interpolation  with  the  use  of  the  available 
data  it  can  be  sketched.  After  the  first  few  days,  when  the  utiliza- 
tion of  the  stored  protein  and  glycogen  provoke  irregularities,  the 
heat  production  is  remarkably  constant.  Most  fasting  bodies  have 
produced,  under  controlled  conditions  of  external  temperature  and 
muscular  work,  from  28  to  33  Calories  per  kilo  per  day;  at  complete 
body  rest  the  figure  will  fall  to  25  Calories.  When  the  oxygen  con- 
sumption and  the  carbon  dioxid  output  of  the  fasting  subject  are 
measured  from  the  third  to  possibly  the  tenth  day,  the  most  marked 
constancy  is  exhibited.    Then  the  tendency  to  lessened  heat  produc- 


INANITION  485 

tion  becomes  apparent.  The  caloric  output  per  kilo  may  remain  the 
same;  but  as  the  individual  is  losing  weight,  the  total  heat  production 
is  falling.  This  reduction  in  total  heat  production  will  not  be  over 
200  or  300  Calories  per  day.  One  might  expect  that  when  the  body 
is  put  to  stress  for  fuel,  the  mechanism  of  physical  regulation  would 
develop  unusual  effectiveness  in  operation  to  the  maximum  of  the 
factors  that  diminished  surface  radiation;  but  there  is  little  sign  of 
such  an  adaptation.  There  is  no  reduction  in  the  basal  production 
of  heat,  even  at  high  external  temperature  and  in  extreme  emaciation. 
We  have  data  bearing  on  under-nutrition  in  which  the  total  heat  pro- 
duction is  notably  lower  than  in  fasting.  Is  it  here  again  the  presence 
of  sugar  that  determines  the  greater  effectiveness  of  the  metabolism? 
Both  animals  and  man  tend  to  become  lethargic  during  prolonged 
fasting,  and  the  heat  output  due  to  involuntary  muscular  movements 
is  thereby  reduced.  It  is  possible  that  the  reduction  in  total  heat 
production  is  due  to  this  factor  alone. 

Elimination  of  Nitrogen. — The  greatest  interest  in  the  metabolism 
of  inanition  centres  about  the  elimination  of  nitrogen.  The  figures 
in  the  literature  hardly  give  a  fair  picture,  since  usually  only  the  urinary 
nitrogen  is  stated.  The  cutaneous  elimination  of  nitrogen  has  not  been 
estimated  in  starvation,  but  it  may  be  assumed  to  equal  the  normal. 
Including  the  growth  of  hair  and  nails  and  the  loss  of  epithelium, 
the  total  cutaneous  elimination  of  nitrogen  cannot  be  less  than  0.3 
gram  per  day  on  an  average.  Of  the  fecal  nitrogen  in  starvation  we 
are  better  informed.  It  usually  runs  from  0.3  to  0.5  gram  per  day, 
may,  however,  rise  to  0.7  gram.  To  be  added  to  the  urinary  nitrogen 
we  have  therefore,  from  possibly  0.7  to  even  1  gram  of  extrarenal 
output  of  nitrogen  daily.  When  it  is  observed  that  the  urinary  nitrogen 
sometimes  falls  below  3  grams  per  day,  the  magnitude  of  the  correc- 
tion becomes  apparent.  There  are  two  defined  periods  in  the  nitrog- 
enous catabolism  in  starvation,  apart  from  the  terminal  period  that 
will  be  described  separately.  The  first  is  the  period  of  nitrogen  or 
glycogen  storage,  the  preliminary  stage.  As  already  stated,  the  nitrogen 
is  relatively  high  in  the  one  and  low  in  the  other.  During  the  second 
period  the  urinary  nitrogen  falls  progressively.  The  daily  outputs  for  a 
professional  faster,  Succi,  will  serve  as  a  typical  illustration.  They  were 
17;  11.2;  10.55;  10.8;  11.19;  11.01;  8.79;  9.74;  10.05;  7.12;  6.23;  6.84; 
5.14;  4.66;  5.05;  4.32;  5.4;  3.6;  5.7;  3.3;  2.82,  corresponding  during 
the  last  days  to  less  than  20  grams  of  protein.  A  certain  amount  of 
protein  can  be  ingested  without  raising  the  figure  for  the  elimination 
of  nitrogen,  i.  e.,  the  protein  is  completely  retained  to  replace  loss. 
Irregularities  are  present,  just  as  are  to  be  seen  on  a  constant  input; 
but  after  the  first  few  days  a  progressive  diminution  is  manifested. 
The  sulphur  runs  parallel  to  the  nitrogen.  The  elimination  of  phos- 
phorus, however,  rises  relatively,  supposedly  due  to  the  solution  of 
bone  rather  than  to  increased  nucleic  catabolism,  because  the  calcium 
output  rises.    From  the  data  on  the  elimination  of  nitrogen  in  the  urine 


486  METABOLISM  CONSIDERED  AS  A   WHOLE 

we  learn,  therefore,  that  the  catabolism  of  the  body  protein  in  estab- 
lished fasting  falls  to  less  than  half  the  figure  known  to  represent  the 
minimum  of  equilibrium  on  a  protein-sugar  diet  covering  the  caloric 
needs  of  the  body.    This  fact  holds  for  man  and  the  dog. 

In  the  rabbit  and  guinea-pig,  however,  the  elimination  of  urinary 
nitrogen  remains  relatively  constant  or  rises  from  the  beginning  of 
fasting  until  death. 

The  partition  of  nitrogen  reveals  interesting  facts.  The  greatest 
reduction  lies,  of  course,  in  the  nitrogen  of  urea,  since  all  the  exogenous 
urea  is  excluded.  As  the  nitrogen  falls,  the  percentage  of  urea  N  falls 
also,  so  that  at  the  lowest  level  the  urea  N  makes  up  55  to  60  per  cent, 
of  the  urinary  nitrogen.  This  figure,  however,  is  often  really  much 
lower  than  it  would  be  were  it  not  for  the  occurrence  of  acidosis,  which 
withdraws  ammonia  and  thus  lowers  the  figure  for  urea.  The  purin 
output  falls  slowly  during  the  period  of  fasting,  but  is  not  strikingly 
below  what  may  be  observed  on  a  milk  diet.  The  creatin-creatinin 
(both  are  present)  is  very  constant  though  well  above  the  figure  for 
endogenous  creatinin;  the  earlier  observations  on  this  subject,  that 
read  to  the  contrary,  were  not  reliable.  The  constancy  of  this  elimina- 
tion when  related  to  the  muscle  content  of  the  fasting  body  is  one  of 
the  striking  demonstrations  of  the  autogeny  of  this  metabolism.  The 
ammonia  would  be  low  if  acidosis  were  not  present.  Sometimes  this 
is  the  case;  in  Succi,  the  urine  on  the  twentieth  day  contained  only 
a  little  over  0.1  gram  of  ammonia.  The  ammonia  output  in  starva- 
tion may  be  lower  than  the  urinary  content  in  ketonic  acids  would 
seem  to  require.  But  the  urine  in  starvation  contains  an  excess  of 
potassium,  which  naturally  is  available  to  the  ketonic  acids.  Hippuric 
acid  is  absent. 

The  curve  of  nitrogen  elimination  in  time  seems  to  be  quite  near 
a  straight  line,  lowest  at  night.  This,  together  with  the  data  on 
partition  and  the  figures  on  the  total  urinary  elimination,  constitute 
strong  arguments  for  the  rigid  application  of  the  distinction  between 
endogenous  and  exogenous  nitrogenous  metabolism  in  normal  nutrition. 

Metabolism  of  Carbohydrate. — The  metabolism  of  carbohydrate  is 
reduced  to  the  lowest  plane.  Little  or  no  sugar  is  burned,  and  the 
glycogen  depots  are  progressively  depleted,  though  at  death  glycogen 
is  still  to  be  found  in  the  tissues.  The  concentration  of  glucose  in 
the  blood  persists,  and  this  must  be  derived  from  protein.  When  the 
catabolism  of  protein  yields  only  3  grams  of  nitrogen  per  day,  this 
would  correspond  to  10  grams  of  glucose,  an  amount  that  the  body 
could  readily  burn  under  the  conditions  of  the  experiment,  without 
leaving  its  mark  on  the  respiratory  quotient.  As  will  be  later  pointed 
out,  in  protein  hunger  with  liberal  carbohydrate  input,  the  nitrog- 
enous output  may  be  reduced  below  the  lowest  figure  ever  to  be  seen 
in  starvation;  and  this  difference  may  be  due,  in  part,  to  a  fraction  of 
protein  catabolized  in  starvation  to  yield  glucose. 


INANITION  487 

Combustion  of  Fat. — The  combustion  of  fat  is  usually  defective, 
in  that  the  ketonic  bodies  may  be  eliminated  in  the  urine  in  rather 
large  amounts.  Indeed,  starvation  is  one  of  the  classic  illustrations 
of  acidosis.  The  amount  of  acetone  bodies  is  often  large  contrasted 
with  the  magnitude  of  the  fat  combustion.  Thus  Succi  had  often  as 
much  as  10  grams  of  b-oxy-butyric  acid  when  he  was  burning  not  over 
150  grams  of  fat,  an  amount  that  the  normal  individual  burns  with 
ease.  The  reason  for  the  difference  lies  in  the  paucity  of  carbohydrate 
in  the  body.  In  some  cases,  however,  the  acidosis  is  practically  nil, 
related  possibly  to  an  abnormally  persistent  retention  of  glycogen 
within  the  tissues.  The  effect  of  administering  fat  to  a  fasting 
animal  not  yet  much  reduced  in  body  fat  is  slight;  later,  it  has  a  more 
noticeable  effect  on  the  metabolism  of  protein. 

Respiratory  Quotient. — The  respiratory  quotient  in  fasting,  after  the 
first  days,  corresponds  to  that  usually  seen  when  the  heat  production 
is  maintained  by  the  combustion  of  fat  and  protein;  0.74  was 
repeatedly  observed  in  the  studies  of  one  starving  man.  In  other 
words,  it  corresponds  to  that  noted  in  the  diabetic  who  cannot  burn 
glucose  and  fires  with  fat  and  protein.  But  in  the  case  of  the  diabetic, 
the  sugar  formed  from  the  exaggerated  protein  catabolism  is  lost, 
while  in  fasting  it  is  utilized. 

With  the  onset  of  the  terminal  or  premortal  period,  the  metabolic 
picture  changes.  The  nitrogen  in  the  urine  rises  sharply,  acidosis  is 
usually  very  pronounced,  and  the  chlorion  that  has  been  tenaciously 
retained,  is  suddenly  increased  in  amount  in  the  urine.  The  premortal 
rise  in  the  protein  catabolism  is  probably  due  to  the  extreme  depletion 
of  the  glycogen;  while  in  many  cases  it  seems  directly  associated  with 
the  reduction  of  fat,  in  other  cases  the  animal  dies  with  characteristic 
symptoms  while  the  body  contains  considerable  fat.  Be  the  cause 
one  or  both,  the  body  turns  to  its  cellular  protein  for  dynamogenetic 
purposes,  and  with  the  cells  attenuated  to  the  last  degree,  such  inroads 
cannot  be  long  borne.  It  is  possible  that  here,  as  is  sometimes  the  case 
with  pathological  autolysis,  the  total  heat  production  may  show  an 
actual  rise. 

Muscular  Work. — When  muscular  work  is  accomplished  during 
inanition,  it  is  done  on  combustion  of  fat,  at  least  this  seems  to  be  the 
rule  in  fasting  men.  Dogs  sometimes  show  a  sharp  rise  in  the  elimina- 
tion of  nitrogen  after  exercise,  indicating  that  protein  had  been  catab- 
olized.  It  is  known  that  a  dog  can  work  hard  on  protein  alone.  But 
with  choice,  doubtless  it  may  be  inferred  that  work  will  be  done  on 
the  combustion  of  fat.  In  the  late  stages  when  fat  storage  is  low,  the 
protein  must  be  drawn  upon.  It  is  probable  that  the  efficiency  of 
work  (the  amount  of  work  accomplished  in  relation  to  the  heat  pro- 
duced) is  lowered  during  inanition.  The  body  temperature  is  normal, 
until  the  terminal  stage,  when  with  falling  heat  production,  even  the' 
most  efficient  restriction  of  heat  dissipation  cannot  maintain  the  body 
temperature  and  it  falls. 


488  METABOLISM  CONSIDERED  AS  A   WHOLE 

Blood. — The  blood  in  starvation  maintains  a  striking  constancy. 
The  concentration  of  glucose  and  protein,  as  well  as  red  corpuscles 
and  their  hemoglobin  content,  remain  quite  normal.  It  has  been 
stated  that  the  serum  globulin  is  increased  relatively  to  the  serum 
albumin,  supposedly  as  the  result  of  the  abstraction  of  globulin  from 
the  organs.  The  fat  is  usually  increased,  and  the  liver  is  well  infiltrated 
with  fat.  This  lipemia  is,  of  course,  simply  the  expression  of  the  trans- 
portation of  fat  from  the  depots  to  the  organs  of  combustion.  The 
protein  concentration  of  the  blood  is  maintained  by  the  abstraction 
of  organ,  muscle  and  connective-tissue  proteins  from  their  native 
sites  and  their  transfer  into  the  circulation.  But  these  do  not  circulate 
as  native  proteins;  they  are  converted  into  serum  albumin  and  serum 
globulin.  As  such  they  are  the  substrate  upon  which  the  essential 
anabolic  processes  of  the  cells,  the  up-keep  and  wear-and-tear,  are 
founded.  The  sugar  is  also  derived  from  the  protein.  The  persistence 
with  which  the  blood  retains  its  constituents  may  be  shown  in  experi- 
ment. If  a  dog  be  bled  the  maximum  amount  of  blood  that  can  be 
taken,  and  the  identical  volume  of  salt  solution  returned  into  the  circula- 
tion, within  a  half  hour  a  sample  of  blood  will  show  that  the  protein 
and  sugar  content  of  the  blood  have  been  restored  to  the  normal. 

Body  Weight. — The  body  weight  is  usually  greatly  reduced  at  the 
close  of  fatal  fasting.  There  is,  however,  little  uniformity  in  the  results 
in  different  species  and  even  in  different  animals  of  the  same  species. 
Sometimes  animals  die  after  relatively  short  fasts  and  the  fat  depots 
and  muscles  of  the  body  are  quite  well  preserved.  In  other  instances 
life  is  preserved  until  emaciation  has  become  most  profound.  Evidently 
the  cause  of  death,  even  in  the  absence  of  demonstrable  intercurrent 
disease,  to  which  fasting  animals  must  be  especially  susceptible,  is  not 
single.  The  total  loss  of  weight  in  animals  varies  from  30  to  60  per 
cent,  of  the  original  weight.  The  loss  in  body  weight  is  greatest  in 
dogs  that  were  not  very  fat  at  the  commencement  of  starvation.  The 
loss  of  body  protein  will  vary  from  20  to  50  per  cent,  of  the  initial 
content.  The  loss  in  body  fat  will  vary  from  30  to  90  per  cent.  These 
marked  differences  indicate  that  the  course  of  starvation  is  very 
irregular  in  different  animals.  In  some  cases  the  animals  die  of  pure 
inanition,  life  lasts  as  long  as  there  is  any  fat  to  burn  and  in  the  last 
few  days  excessive  combustion  of  the  sole  remaining  fuel,  protein,  leads 
to  a  marked  premortal  rise  in  the  nitrogenous  output.  In  other 
cases  certain  organs,  as  the  heart,  seem  to  give  out  long  before  fuel  is 
exhausted.    Possibly  the  age  of  the  animal  may  be  a  factor  of  influence. 

Behavior  of  Organs  and  Tissues. — The  behavior  of  the  different 
organs  and  tissues  illustrates  the  diverse  resistance  of  the  several 
cells.  The  eyes  and  skeleton  lose  the  least  in  weight,  not  over  5  per 
cent.  The  heart,  skin  and  total  mass  of  blood  are  reduced  possibly 
one-sixth,  though  the  figure  for  the  blood  has  been  calculated  much 
higher  and  is  obviously  difficult  of  determination.  The  same  figure 
holds  for  the  brain;  for  a  time  the  central  nervous  system  resists  reduc- 


INANITION  489 

tion,  but  later  in  starvation  fat  is  abstracted  in  amounts  that  are 
really  surprising.  The  glands  of  the  body,  as  a  whole,  lose  more  than 
the  muscles,  50  as  against  40  per  cent.  The  loss  of  weight  in  the  liver 
is  all  the  more  marked  when  the  fatty  infiltration  is  taken  into  account. 
The  connective  tissues  are  greatly  wasted,  and  furnish  to  the  glands 
certainly  a  large  amount  of  protein.  In  the  opinion  of  the  writer,  the 
process  of  cellular  sustenance  in  fasting  is  identical  with  the  process 
of  maturation  of  the  sexual  organs  in  anadromous  fish;  the  muscle 
substance  is  catabolized,  the  sexual  glands  utilize  what  is  needed,  and 
the  balance  of  the  amino-acids  are  burned.  So  in  starvation  the  least 
essential  cells  yield  their  protein,  it  is  hydrolyzed,  the  essential  cells 
utilize  what  is  needed  for  anabolism,  and  the  superfluous  amino-acids 
are  burned. 

In  what  may  be  called  successful  experiments  in  fasting,  the  fat 
of  the  body  (disregarding  the  lipoids  of  the  central  nervous  system 
and  referring  to  depot  fat)  is  reduced  to  mere  traces.  The  glycogen 
becomes  reduced  to  traces  but  persists  to  the  last  in  liver  and  the  other 
glands  and  in  muscle.  It  is  not  possible  to  make  an  animal  body 
glycogen-free  by  starvation  and  voluntary  exercise. 

The  wasting  of  a  fasting  body  is  dimensional  and  not  numerical  in 
the  cellular  sense.  While  the  individual  cubic  centimeter  of  blood  is 
normal  in  composition,  it  is  still  possible  that  the  total  mass  of  blood 
in  the  body  is  reduced.  The  number  of  cells  remains  constant,  so  far 
as  can  be  determined ;  even  the  cells  of  the  connective  tissues  that  yield 
most  protein  are  only  greatly  attenuated,  not  obliterated.  The  different 
degrees  of  wasting  in  various  tissues  obviously  expresses  the  different 
degrees  of  intracellular  attenuation.  When  the  animal  is  again  fed 
up,  the  cells  are  restored  to  their  original  dimensions.  The  process 
has  been  strikingly  illustrated  in  experiments  on  the  expression  of 
substance  from  muscle  cells  by  hydraulic  pressure;  under  a  pressure 
of  some  300  to  350  atmospheres  applied  to  fresh  lean  muscle,  no  less 
than  44  per  cent,  of  the  contained  protein  could  be  expressed,  without 
any  change  in  the  microscopic  appearances  of  the  individual  muscle 
cells. 

Protein  Starvation. — When  an  animal  is  deprived  of  protein  and 
given  a  liberal  ration  of  carbohydrate,  more  than  enough  to  cover  the 
heat  production  of  the  body,  we  place  the  nitrogenous  metabolism 
in  a  situation  in  which  the  powers  of  adaptation  of  the  function  are 
strikingly  displayed.  There  are  a  number  of  such  experiments  on  men, 
but  if  the  results  of  more  recent  studies  on  swine  are  applicable  to  man, 
the  periods  of  the  tests  have  been  too  brief.  Apparently  the  protein 
metabolism  does  not  strike  bed  rock,  so  to  speak,  in  less  than  two  weeks, 
and  does  not  before  that  time  exhibit  its  full  powers  of  restriction. 
The  striking  results  are  the  lowness  of  the  output  of  nitrogen,  the 
evenness  of  the  curve  of  urinary  nitrogen  and  the  constancy  of  the 
elimination  of  urea  (plus  ammonia),  creatinin  and  the  purins.  The 
total  nitrogen  in  men  falls  to  about  3  grams,  and  would  probably  fall 


490  METABOLISM  CONSIDERED  AS  A   WHOLE 

in  a  longer  test  to  less  than  2  grams.  The  urea-ammonia  make  up 
about  55  to  60  per  cent,  of  the  total  nitrogen,  the  creatinin  about  17 
to  20  per  cent.  The  ammonia  is  low,  as  there  is  no  acidosis.  Evidently 
we  have  here,  as  clearly  as  the  experiment  can  reveal  them,  the  basal 
nitrogenous  requirements  of  the  body  for  up-keep  and  wear-and-tear — 
for  the  regeneration  of  the  cells  that  are  daily  undergoing  death  and 
the  wear  and  tear  of  all  functionating  cells.  The  amounts  are  so  low 
as  to  make  it  certain  that  for  a  long  time  the  body  can  secure  protein 
for  the  essential  cells  from  the  non-essential  cells  without  approach 
to  the  limit  of  safety.  If  the  input  of  carbohydrate  be  reduced  below 
the  caloric  requirement,  the  nitrogen  of  the  urine  rises.  Fat  cannot 
be  used  to  supplant  the  carbohydrate  except  to  a  limited  extent.  Pro- 
tein hunger  with  fat  ingestion  would  be  little  different  from  the  early 
stages  of  fasting,  except  that  the  elimination  of  nitrogen  would  be  a 
little  lower.  The  maximum  saving  power  of  carbohydrate  is  exhibited 
in  the  experiment  of  protein  deprivation  with  carbohydrate  ingestion, 
and  it  is  under  these  circumstances  that  we  observe  the  lowest  level 
to  which  the  protein  metabolism  has  been  brought  in  experiment. 
Growth  is  not  possible  in  an  animal  during  the  course  of  such  an  experi- 
ment. If  the  data  be  calculated  to  apply  to  longer  tests,  it  is  apparent 
that  such  a  diet  could  sustain  life  in  man  for  probably  one  hundred 
and  fifty  days,  or  three  times  the  probable  duration  of  life  in  complete 
fasting.  If  protein  be  administered  to  an  animal  in  protein  hunger, 
it  will  be  utilized  most  effectively  the  longer  the  animal  has  been 
deprived  of  protein.  If  a  large  ingestion  be  given,  it  will  be  metabolized 
with  great  rapidity. 

Carbohydrate  Fasting. — Carbohydrate  fasting  amounts  to  the  same 
thing  as  a  protein-fat  diet.  If  the  diet  be  arranged  so  as  to  provide 
just  enough  protein  to  maintain  nitrogenous  equilibrium,  this  will 
be  found  to  be  much  higher  than  in  the  same  subject  on  a  protein- 
carbohydrate  diet.  The  sugar  derived  from  the  catabolism  of  the 
protein  is  sufficient  to  insure  the  normal  combustion  of  fat  (apart 
from  some  acentonuria  possibly)  and  to  protect  the  sugar  concentra- 
tion of  the  blood  and  the  glycogen  stores  of  the  tissues.  The  specific 
dynamic  action  of  such  a  diet  is  high,  just  as  the  plane  of  exogenous 
protein  catabolism  is  high.  It  is  not  to  be  questioned  that  such  a 
diet  may  under  certain  conditions  of  life  be  termed  a  normal  diet. 
It  is  commonly  employed  in  the  polar  regions  and  by  explorers  and 
hunters  in  the  form  of  powdered  dried  meat  and  fat  (pemmican). 
It  is  a  diet  yielding  much  heat  but  making  heavy  demands  on  the 
nitrogenous  metabolism.  It  is  often  employed  by  physicians  to  repair 
depletion  of  tissues  after  disease,  for  which  purpose  it  is  not  adapted, 
since  with  an  isodynamic  input  of  carbohydrate  and  protein,  the  body 
would  lay  on  flesh  much  more  rapidly.  Fat  builds  fat  truly;  but  meat 
does  not  build  meat;  in  the  absence  of  carbohydrate  it  simply  yields 
heat  and  throws  upon  the  body  the  burden  of  catabolism  of  excess 
of  protein  and  elimination  of  the  end  products. 


INANITION  491 

Fat  Starvation. — This  is  the  same  state  as  a  protein-carbohydrate 
diet.  Upon  such  a  regimen  the  body  will  establish  nitrogenous  equilib- 
rium on  a  low  level,  not  over  6  or  7  grams  per  day.  Such  a  diet  is 
experimentally  almost  ideal;  it  yields  a  large  amount  of  energy  with 
the  minimum  of  metabolic  work.  The  specific  dynamic  action  of  the 
diet  is  low,  for  with  the  saving  power  of  sugar  for  protein  the  nitrog- 
enous metabolism  is  low.  Since  the  body  retains  nitrogen  fully  with 
an  abundance  of  carbohydrate,  repair  of  lost  cellular  protein  and  fleshen- 
ing  of  every  kind  is  well  accomplished.  The  reaction  for  the  formation 
of  fat  from  sugar  insures  the  proper  storage  of  fat  in  the  body.  The 
ration  of  carbohydrate  is,  however,  rather  large  for  some  individuals, 
who  suffer  from  fermentative  carbohydrate  dyspepsia.  In  the  world 
of  experience  outside  the  experimental  laboratory,  the  absence  of 
fat  from  the  diet  is  known  to  carry  with  it  elements  of  danger.  In 
infants  particularly  the  fat-free  or  fat-low  diet  is  known  to  predispose 
to  rachitis  and  to  subnutrition.  And  in  large  masses*  of  population 
subsisting  on  diets  nearly  free  of  fat,  a  tendency  to  undernutrition 
seems  certainly  to  be  apparent.  Experimentally  it  is  possible  to  nearly 
free  the  animal  body  of  depot  fat  by  feeding  with  protein  and  carbo- 
hydrate only  in  quantity  sufficient  to  cover  the  minimal  nitrogenous 
needs,  leaving  the  caloric  wants  largely  unprovided  for.  If  the  experi- 
ments are  carefully  done,  the  body  will  be  made  almost  free  of  depot 
fat,  while  the  tissues  have  lost  but  little  nitrogen.  This  experiment 
is  duplicated  in  the  rigorous  reduction  of  obesity;  and  experience  has 
taught  that  danger  attends  the  procedure. 

Flesh  Diet. — The  dog  will  subsist  indefinitely  on  meat  and  for  experi- 
mental periods  on  protein  plus  salts.  Man  also  is  able  to  live  on  flesh 
alone.  It  is  at  first  a  tax  on  the  organs  of  digestion,  it  is  certainly  a 
tax  upon  the  organs  of  nitrogenous  elimination;  it  is  at  all  times  a  very 
wasteful  and  extravagant  diet  and  one  that  weight  for  weight  does 
not  support  heat  or  work  well,  but  can  be  tolerated,  especially  in  out- 
door life,  for  long  periods  of  time.  The  preference  of  barbarians  for 
the  flesh  diet  has  no  physiological  meaning.  The  testimony  of  explorers 
and  sportsmen  who  have  chosen  or  been  compelled  to  live  on  flesh 
is  to  the  effect  that  once  experienced  it  will  never  again  be  the  diet 
of  choice,  but  only  of  final  and  inexorable  necessity.  The  greater 
the  heat  demands  upon  the  organism,  the  more  onerous  and  unsatis- 
factory the  diet  becomes. 

The  input  of  protein  required  to  reach  and  maintain  balance  in 
nitrogen,  in  the  absence  of  carbohydrate  and  fat  in  the  diet,  is  three 
to  four  times  the  amount  of  protein  required  in  starvation  of  medium 
length.  In  other  words,  nitrogenous  equilibrium  would  not  be  estab- 
lished on  less  than  an  input  of  20  to  25  grams  of  nitrogen.  At  the 
most  such  a  diet  would  offer  no  more  than  600  Calories  of  heat,  leaving 
an  enormous  deficit.  If  now  the  input  of  protein  be  progressively 
increased,  the  figures  of  nitrogen  output  will  ascend  proportionately, 
more  and  more  heat  will  be  thus  derived  and  the  combustion  of  body 


492  METABOLISM  CONSIDERED  AS  A   WHOLE 

fat  correspondingly  reduced.  When  the  input  of  protein  is  so  augmented 
as  to  cover  the  caloric  needs  of  the  body,  the  nitrogenous  metabolism 
will  be  in  equilibrium  on  a  very  high  level  and  the  body  heat  will  be 
supported  by  the  dynamogenetic  combustion  of  protein.  If  more  protein 
be  ingested  a  certain  storage  may  take  place ;  and  in  a  curious  manner, 
to  the  excessive  specific  dynamic  action  of  the  enormous  ration  of 
protein  is  added  a  further  tendency  to  exaggerate  the  total  heat  pro- 
duction in  a  relative  manner.  If  to  a  diet  of  excessive  protein,  carbo- 
hydrate be  added  largely,  the  body  can  be  induced  to  retain  rather 
large  amounts  of  the  protein,  in  one  state  or  another — to  lose  it  again 
so  soon  as  the  input  is  reduced.  To  cover  the  caloric  requirements 
of  a  man  of  70  kilos  at  moderate  work  living  on  a  flesh  diet,  not  less 
than  750  grams  of  protein  must  be  ingested,  with  a  nitrogen  content 
of  120  grams.  The  striking  discrepancy  between  the  specific  and 
the  dynamogenetic  properties  of  protein  are  brought  out  in  these 
figures.  Under  the  most  favorable  conditions,  protein  will  support 
nitrogenous  balance  on  an  input  of  5  grams  of  nitrogen  per  day;  but 
to  support  the  body  heat,  twenty  or  twenty-five  times  as  much  protein 
are  required.  From  the  sugar  derived  from  this  protein  the  body  will 
easily  maintain  its  stores  of  glycogen,  and  some  fat  may  be  laid  on. 
But,  as  a  matter  of  fact,  it  would  be  difficult  to  select  another  diet  that 
would  lay  on  as  little  flesh  and  fat  as  a  pure  meat  diet.  Entirely  apart 
from  the  consideration  of  the  dynamogenetic  aspect  of  the  diet,  the 
enormous  labor  imposed  on  the  catabolism  of  protein  and  the  elimina- 
tion of  the  end  products  renders  the  diet  highly  undesirable.  Even 
in  the  pure  carnivora,  the  experience  of  breeders  and  trainers  of  dogs 
is  unanimous  to  the  effect  that  a  pure  meat  diet  is  unadapted  to  the 
best  functionation  of  these  animals,  as  well  as  to  their  best  growth 
and  work.  A  dog  will  work  on  a  pure  meat  diet  and  labor  hard  if  forced. 
But  coursing  trainers  have  long  made  the  experience  that  "meat  gives 
no  wind;"  in  other  words,  the  maintenance  of  work  is  accomplished 
even  in  carnivora  in  the  most  effective  manner  on  a  diet  composed  of 
a  moderate  ration  of  protein  and  a  large  input  of  carbohydrate. 

Forced  Feeding. — The  ingestion  of  heavy,  excessive  rations  of  sugar 
and  fat  lead  simply  to  storage.  No  exaggeration  of  the  combustion  of 
these  substances  follows  the  ingestion  of  amounts  in  excess  of  require- 
ments; nor  is  the  protein  metabolism  materially  affected.  On  full 
protein  ration,  excess  of  sugar  and  fat  have  little  effect  in  saving  protein; 
they  have  no  effect  in  exaggerating  the  catabolism  of  protein  or  of  the 
total  heat  production  of  the  body.  From  this  it  follows  that  if  the 
processes  of  digestion  are  normal,  it  ought  to  be  possible  to  fatten  every 
resting  individual.  Now  rarely  an  individual  is  encountered  in  whom 
despite  excessive  resorption  of  sugar  and  fat,  no  fattening  occurs. 
Unless  such  a  result  can  be  explained  on  the  basis  of  excessive  loss  of 
heat  through  individualism  in  the  mechanism  of  physical  regulation, 
it  is  possible  to  assume  that  in  these  subjects  the  body  treats  fat  and 
sugar  in  the  same  way  as  all  bodies  react  toward  ingestion  of  exogenous 
protein— all  is  catabolized.    Experimental  data  are  lacking. 


THE  NORMAL  DIET  493 


THE   NORMAL   DIET 


About  the  fraction  of  protein  centre  the  problems  of  a  normal  diet. 
Recent  years  have  contributed  greatly  to  the  clarification  of  these 
questions.  In  particular,  the  definition  of  the  physiological  minimum 
of  protein  intake  has  been  accomplished.  The  earlier  ideas  on  the  pro- 
tein ration  of  a  normal  diet  were  derived  from  statistical  observation. 
The  more  recent  ideas  are  founded  upon  thorough  physiological  experi- 
mentation. The  earlier  standard  diets  were  rich  in  protein.  The 
experimental  diets  are  relatively  poor  in  protein.  Before  taking  up 
the  consideration  of  the  experimental  data,  it  is  necessary  to  define 
a  diet  and  then  to  consider  the  merits  of  the  statistical  method  of 
fixing  the  components. 

Desiderata  for  Diet. — A  diet  must  fulfil  many  desiderata,  and  these 
are  better  expressed  in  sentences  than  in  subdivisions  of  a  sentence. 
A  diet  must  first  of  all  maintain  a  nitrogenous  equilibrium  in  the  body. 
It  must  yield  to  all  the  cells  of  the  body  such  a  complete  series  of  the 
amino-acids  and  such  abundance  of  these  as  to  enable  the  anabolic 
and  wear-and-tear  processes  to  be  accomplished  with  the  highest  effi- 
ciency and  with  the  least  metabolic  exertion.  It  must  provide  materials 
for  anabolism  of  protein  in  gestation,  in  lactation  and  during  growth. 

A  diet  must  contain  energy-bearing  foods  sufficient  to  maintain 
the  caloric  equilibrium  of  the  individual  under  his  conditions  of  life. 
The  division  of  the  carbonous  foods  between  fat  and  carbohydrate 
will  rest  to  a  considerable  extent  upon  the  taste  and  purchasing  power 
of  the  individual.  The  law  of  isodynamic  values  in  these  foodstuffs 
is  the  foundation  of  the  diet,  in  the  economic  sense. 

A  diet  must  satisfy  the  reasonable  demands  of  taste  and  bulk.  It 
must  provide  variety  in  order  to  satisfy  taste,  for  variety  is  as  essential 
to  appetite  as  is  the  most  toothsome  preparation  of  food.  It  must 
provide  a  certain  bulk,  because  the  physical  sensations  of  satiation 
are  to  some  extent  dependent  on  bulk;  and  bulk  means  also  residue 
for  the  formation  of  the  feces. 

A  diet  must  contain  to  a  certain  extent  fresh  or  at  least  raw  foods, 
upon  the  absence  of  which  marked  disturbances  of  nutrition,  such  as 
scurvey,  are  known  to  rest,  though  the  mechanism  of  these  abnormalities 
is  unknown. 

A  diet  should  contain  a  certain  fraction  of  vegetable  fiber.  Cellulose 
aids  in  the  physical  management  of  the  intestinal  contents,  prevents 
caking,  renders  the  intestinal  mass  more  porous  and  thus  facilitates 
resorption  and  furnishes  a  bulk  to  the  stools,  of  great  advantage  to 
regular  defecation. 

A  diet  must  contain  the  salts  needed  by  the  body,  in  the  qualitative 
and  quantitative  sense.  This  is  the  great  advantage  of  the  mixed 
diet,  the  salt  needed  are  reliably  contained  only  in  such  a  diet.  A  diet 
ought  not  to  contain  an  excess  of  salts  or  of  one  kind.   The  use  of  table 


494  METABOLISM  CONSIDERED  AS  A   WHOLE 

salt  in  the  diet,  as  developed  under  modern  tastes,  is  not  physiological 
but  gustatory  and  is  often  carried  to  excessive  and  injurious  extent. 

Lastly,  a  diet  should  contain  extractive  substances  and  flavoring 
materials  that  stimulate  the  secretion  of  gastric  juice.  The  importance 
of  early  and  normal  secretion  of  gastric  juice  to  intestinal  secretion 
and  digestion  has  been  dilated  upon.  Bland  diets  of  simple  foodstuffs 
are  apt  to  fail  in  stimulation  of  gastric  secretion,  at  least,  under  modern 
conditions  of  life.  An  excess  of  extractives,  however,  is  to  be  avoided, 
since  they  tend  to  replace  nutrients.  The  fault  of  the  modern  diet 
is  in  many  instances  that  it  has  flavors  but  lacks  calories. 

A  diet,  in  components  and  in  every  way,  must  be  adapted  to  the 
age,  sex,  occupation  and  external  climatic  relations  of  life.  A  serious 
infraction  of  this  dictum  is  rarely  to  be  noted,  except  under  cruel 
exigencies  of  want  or  isolation.  In  modern  society,  the  exaggeration 
of  the  point  of  view  of  taste  and  the  existence  of  preconceptions  have 
led  to  the  externalities  of  the  diet  being  given  such  consideration  over 
the  internalities  of  the  diet  as  to  make  many  questions  of  diet  financial 
rather  than  physiological.  The  physical  and  chemical  requirements  of 
a  diet  are  nowadays  but  a  small  fraction  of  the  food  requirements 
of  the  diet,  using  the  term  in  its  external  sense.  It  is  no  exaggeration 
to  state  that  our  people  could  be  physiologically  nourished  on  a  fourth 
of  the  present  financial  outlay  for  the  diet.  The  esthetics  of  the  diet 
have  assumed  almost  complete  control  over  the  energetics  of  the  diet. 
Subnutrition  is  not  the  result,  overnutrition  rather.  But  it  has  led 
to  the  overcapitalization  of  the  function  of  nourishment  and  has  from 
this  point  of  view  established  conditions  of  serious  sociological  and 
industrial  import. 

Amount  of  Protein  Required. — The  standard  diet  defined  by  the 
statistical  method  allows  from  115  to  150  grams  of  protein  per  day. 
The  theory  of  judging  a  diet  by  the  data  of  the  statistical  method 
rests  upon  the  broad  foundation  that  instinct  and  appetite  are  spokes- 
men of  physiological  needs;  and  when  through  generations  of  racial 
observation  and  individual  experience,  the  consumption  of  food  dis- 
plays a  certain  mean,  it  may  be  taken  for  granted  that  this  is  the  best 
figure  in  a  diet.  The  modern  diet,  in  a  sense,  is  regarded  as  an  expres- 
sion of  the  survival  of  the  fittest.  So  far  so  good,  and  there  can  be  no 
objection  to  the  general  standpoint  herein  stated.  But  when  we  come 
to  analyze  the  facts,  the  generalization  as  stated  is  seen  to  lose  much 
of  its  force.  For  it  is  easy  to  demonstrate  that  many  other  factors 
than  physiological  experience  have  been  potent  in  moulding  the  dietetic 
notions  of  a  people.  Religious  rites  are  closely  connected  with  diets. 
Will  anyone  contend  that  the  ritual  as  related  to  diet,  be  it  in  the 
savage  tribe  or  in  the  modern  church,  is  in  any  way  expressive  of 
physiological  needs?  We  have  developed  from  barbarians  who  followed 
the  chase  partly  because  it  was  the  most  easy  method  of  securing  food, 
partly  because  the  instinct  to  prey  was  native  in  the  savage  breast. 
Geographical  considerations  and  climatic  factors  have  modified  largely 


THE  NORMAL  DIET  495 

but  irregularly  the  development  of  the  race  from  savagery  through 
barbarianism  to  civilization.  In  some  lands  races  were  compelled  to 
adopt  cultivation  of  the  soil,  in  other  places  fishery;  in  some  areas,  the 
chase  remained  long  into  relative  civilization  one  of  the  chief  methods 
of  securing  food.  The  variations  in  ethnological  development  brought 
about  by  enforced  cultivation  of  the  soil,  as  contrasted  with  the  state 
of  affairs  in  a  tribe  of  hunters,  are  well  illustrated  in  different  tribes 
of  our  American  Indians.  Depending  upon  the  method  of  sustaining 
the  life  of  the  tribe,  the  standard  diet  of  the  tribe  varied.  Only  under 
modern  conditions  of  transportation  have  the  instincts  and  tastes 
of  man  had  opportunity  for  full  choice  in  diet.  Compulsion  to  some 
extent  and  in  some  degree  there  has  always  been.  Customs  and  racial 
preferences  and  prejudices  are  reflected  in  the  diet  of  a  modern  people. 
Dependence  on  raw  and  red  meat,  still  to  be  noted  in  the  diet  of  the 
prize  fighter,  runs  back  to  the  days  of  the  chase  when  red  blood  and 
flesh,  for  man  and  hound,  meant  strength,  courage  and  endurance. 
A  survey  of  the  development  of  taste  in  foods  through  the  centuries 
and  a  correlation  of  diet  customs  with  the  available  foodstuffs  of  the 
time  do  not  lend  much  color  to  the  hypothesis  that  the  development 
of  customs  in  diet  have  been  materially  guided  by  the  experience  of 
the  race  in  the  concrete  physiological  sense.  According  to  the  best 
information,  the  following  figures  represent  in  grams  the  meat  consump- 
tion per  day  in  the  named  countries:  Australia,  300;  United  States,  150; 
England,  130;  France,  90;  Netherlands,  85;  Austria  Hungary,  80; 
Russia,  60;  Spain,  60;  Italy,  30;  Japan,  25.  These  figures  do  not 
afford  much  support  to  the  idea  that  the  protein  consumption  of  a 
race  corresponds  to  work  or  metabolic  needs.  Practically  every  native 
race  has  discovered  alcoholic  fermentation.  Is  this  an  argument  for 
the  physiological  value  of  alcohol? 

Leaving  the  general  question,  one  concrete  appeal  to  the  statistical 
method  here  concerns  us.  It  is  contended  that,  as  a  rule4  the  working 
classes  increase  the  input  of  protein  when  work  is  increased;  that  the 
diet  of  the  working  classes  is  richer  in  protein  than  that  of  the  leisure 
classes.  Naturally,  the  statement  is  made  with  the  restriction  that  the 
working  classes  concerned  must  have  choice  in  the  selection  of  the 
diet.  As  a  matter  of  fact,  it  is  not  true  that  working  classes  raise  the 
input  of  protein  when  working  hard ;  the  world  over  the  price  of  protein 
is  such  as  to  make  choice  in  protein  input  very  restricted.  The  German 
peasant,  the  oriental  coolie,  the  Italian  laborer,  the  Slav  farmer,  the 
cane  cutter  on  the  Gulf  plantations  statistically  do  not  consume  much 
protein;  on  the  contrary,  the  diet  of  these  classes  serves  better  to  illus- 
trate on  how  little  protein  men  may  subsist  and  work.  That  under- 
nutrition exists  in  all  these  classes  is  probable;  but  the  cause  of  this 
undernutrition  cannot  be  single,  it  has  many  elements.  It  is  true, 
however,  that  in  this  country  and  in  England,  the  popular  ideal  of 
diet  for  the  working  classes  includes  a  high  ration  of  protein.  The 
American  farmer  knows  the  value  of  fat  in  the  diet,  knows  it  too  well 


496  METABOLISM  CONSIDERED  AS  A   WHOLE 

in  fact,  since  with  the  conditions  under  which  he  works  carbohydrates 
would  be  in  part  preferable.  The  diets  of  our  farming  folk  are  rich 
in  protein.  The  same  is  true  of  the  diet  of  lumbering  and  construction 
camps.  But  at  the  most  the  nitrogen  input  of  the  working  classes  does 
not  equal  that  of  the  leisure  classes — a  statement  of  fact  as  true  here 
in  the  land  of  choice  as  in  Europe  where  choice  in  the  diet  is  largely 
confined  to  the  leisure  classes.  The  leisure  classes  eat  meats  because 
the  flavors  stimulate  the  jaded  tastes  and  appetite,  and  because  the 
cuisine  of  meats  is  more  highly  developed  than  is  the  cuisine  of  vegetables. 
The  laborer  eats  protein  heavily  simply  because  he  eats  heavily  of  every 
thing,  and  naturally  consumes  a  goodly  ration  of  albumin.  The  only 
individuals  who  elect  a  heavy  protein  diet  with  the  idea  of  its  support- 
ing qualities  are  athletes.  It  is  a  fair  question,  since  the  predilection 
for  a  heavy  meat  ration  is  confined  to  Anglo-Saxon  athletes,  whether 
this  is  not  the  direct  descendant  of  the  old  red  meat  and  blood  notion 
of  the  Englishman.  Athletes  in  numbers  in  our  country  have  demon- 
strated the  perfect  reliability  of  the  low  protein  diet  for  the  most  severe 
athletic  contests.  Masters  of  coursing  hounds  long  ago  discovered 
that  meat  is  not  the  best  food  for  the  dog,  but  that  a  diet  moderate 
in  protein  and  rich  in  carbohydrate  gives  the  longest  wind  and  strongest 
leap. 

Protein  Content  of  Milk. — The  most  striking  statistical  evidence  bear- 
ing on  the  question  lies  in  the  protein  content  of  milk.  This,  however, 
is  not  in  favor  of  but  is  opposed  to  the  idea  of  a  high  input  of  protein 
in  the  standard  ration.  There  are  marked  variations  in  the  protein 
content  of  the  milk  of  different  animals,  but  perhaps  the  most  striking 
fact  is  the  low  protein  content  of  human  milk.  The  milk  of  canines 
and  felines  is  very  rich  in  protein;  that  of  cattle,  sheep,  and  goats  is 
moderately  rich,  that  of  horses  poor,  that  of  woman  probably  poorest 
of  all.  Yet,  of  course,  these  various  milks  are  adapted  to  the  nourish- 
ment and  growth  of  the  young  of  each  species.  It  is  a  fair  argument 
that  the  amount  of  protein  relatively  necessary  in  the  diet  of  the  grow- 
ing infant  may  be  taken  as  an  amount  fully  competent  in  the  adult. 
To  the  mind  of  the  writer,  the  sole  escape  from  this  conclusion  must 
rest  upon  some  hypothesis  that  the  dynamogenetic  utilization  of  pro- 
tein possesses  a  peculiar  and  exceptional  value.  "Blut  ist  ein  ganz 
besonderer  Saft."  But  unless  it  can  be  shown  that  in  the  conversion 
of  potential  energy  into  work,  protein  is  peculiarly  superior  to  sugar 
and  fat,  the  protein  input  per  unit  in  infancy  must  be  regarded  as  the 
maximum  coefficient,  since  at  no  other  time  of  life  are  such  demands 
made  upon  the  anabolic  functions. 

Protein  and  Anabolic  Function. — Physiological  experimentation,  on 
the  other  hand,  is  based  upon  the  proposition  that  protein  in  the  body 
is  needed  in  the  functions  of  anabolism  in  the  regenerative  processes 
and  to  maintain  the  status  quo  of  protoplasm,  the  wear-and-tear  of 
the  cells  and  tissues.  Based  upon  the  isodynamic  law,  the  fuel  value 
of  protein  is  judged  as  fat  and  sugar  are  judged.     Experiments  have 


THE  NORMAL  DIET  497 

been  carried  out  in  extenso  to  define  the  essential  cellular  fraction 
of  protein  metabolism,  and  to  separate  it  from  the  dynamogenetic 
fraction  of  protein  metabolism.  It  is  conceded,  on  the  basis  of  known 
powers  of  compensation  and  adaptation,  that  investigations  to  be 
reliable  must  extend  over  long  periods  of  time,  that  they  must  cover 
every  exigency  of  life,  that  not  only  minimal  but  even  unusual  demands 
upon  the  economy  must  be  fully  met,  and  that  in  addition  a  margin 
of  safety  is  to  be  permitted.  We  are  now  in  possession  of  an  enormous 
literature  bearing  on  the  utilization  of  protein  in  metabolism;  and  the 
definition  of  the  necessary  input  of  protein  under  varying  conditions 
of  life  may  now  be  made.  The  conclusions  of  the  physiological  investiga- 
tions have  contradicted  the  inferences  drawn  from  statistical  surveys. 

Catabolism  of  Protein  in  Inanition. — In  the  study  of  inanition  we 
learned  that  the  catabolism  of  protein  within  the  body  can  be  separated 
into  several  fractions,  (a)  Dynamogenetic  catabolism  for  purposes  of 
heat  production.  This  occurs  for  the  first  few  days  in  starvation.  It 
occurs  in  normal  subjects  when  protein  is  ingested  in  excess  of  cellular 
requirements,  the  catabolism  of  exogenous  protein  is  dynamogenetic. 
(b)  Catabolism  of  indifferent  protein  to  yield  material  for  the  anabolism 
of  the  essential  cells,  (c)  Catabolism  of  indifferent  .protein  to  yield 
sugar  to  maintain  sugar  concentration  of  the  blood,  (d)  The  essential 
protein  catabolism,  the  catabolism  associated  with  the  wear  and  tear 
and  up-keep  of  the  cells  of  organs  and  tissues.  In  a  normal  diet  the 
input  of  protein  must  cover  fractions  (6)  and  (d).  In  nitrogen  starva- 
tion it  may  be  shown  that  these  two  fractions  comprise  an  amount  of 
protein  that  for  a  man  of  70  kilos  is  represented  by  a  nitrogen  output  of 
not  over  3  grams  per  day.  Viewing  the  matter  from  the  standpoint 
of  protein  content,  rather  than  of  protein  utilization,  we  have  four 
fractions  of  protein  in  the  body,  (a)  The  irreducible  protein  of  the 
cells.  There  is  a  shrinkage  that  is  tolerated  by  every  cell,  but  there 
is  a  point  in  the  reduction  of  protein  content  that  is  fatal,  (b)  The 
fraction  of  protein  that  the  cells  yield  to  demands  in  starvation  or 
nitrogen  hunger — the  protein  between  the  usual  state  of  the  cells  and 
the  irreducible  protein,  (c)  There  is  a  fluctuating  fraction  of  cellular 
protein,  possibly  advantageous  for  good  functionation,  the  fraction  lost 
in  the  first  few  days  of  starvation,  (d)  Lastly,  the  luxury  fraction  of 
protein,  the  protein  that  can  be  induced  to  go  into  the  cell  in  protein 
engorgement,  to  remain  a  longer  or  shorter  time  after  the  excessive 
feeding  is  discontinued.  This  fraction  is  usually  small.  It  is  because 
the  body  refuses  to  store  proteins  that  exogenous  protein  is  usually 
fully  and  promptly  catabolized.  Fractions,  a,  b,  c,  ought  to  be  covered 
by  the  protein  input  of  a  normal  diet. 

Protein  in  Mixed  Diet. — Now  in  a  mixed  diet,  with  usual  amounts 
of  carbohydrate  and  fat,  what  amounts  of  protein  are  required  to 
cover  the  needs  of  the  body  and  to  maintain  the  normal  protein  content 
of  the  fluids  and  cells  of  the  body  as  defined  above?  From  a  large 
number  of  investigations  it  is  certain  that  on  an  average,  a  half  gram 
32 


498  METABOLISM  CONSIDERED  AS  A   WHOLE 

of  protein  per  day  per  kilo  body  weight  is  sufficient  to  accomplish  this. 
This  would  cover  the  body  needs,  maintain  the  normal  state  of  cellular 
protoplasm,  and  impose  no  conditions  on  the  anabolic  or  catabolic 
functions  of  the  cells;  it  would  leave  little  exogenous  protein  to  be 
catabolized,  it  would  provide  little  protein  for  dynamogenetic  purposes. 
The  data  upon  which  these  statements  are  based  are  so  extensive  and 
the  results  in  the  hands  of  numerous  investigators  so  unanimous, 
that  there  can  be  no  escape  from  the  conclusions. 

The  crux  of  the  question  here  appears :  Is  there  warrant  or  necessity 
for  restriction  of  the  role  of  protein  in  metabolism  to  the  function  of 
protein  in  protoplasm?  Has  protein  any  advantages  as  a  mere  fuel? 
Does  the  use  of  protein  as  a  fuel  carry  with  it  any  disadvantages? 
Does  the  figure  stated  above  carry  with  it  a  wide  margin  of  safety, 
for  all  ages,  sexes,  states  and  conditions  of  health  and  disease,  for 
occupational  and  climatic  variations?  Is  the  proposed  restriction 
of  protein  to  the  needs  of  the  nitrogenous  metabolism  a  matter  of 
advantage  or  merely  of  choice,  of  indifference  to  the  body? 

Excessive  Intake  of  Protein. — Does  the  use  of  protein  in  excess  of 
the  cellular  requirements  (dynamogenetic  utilization),  possess  any 
advantages?  The  exogenous  protein  is  hydrolyzed,  the  amino-acids 
deaminizated,  from  a  fraction  of  these  sugar  formed,  the  rest  is  burned. 
The  sugar  formed  from  protein  is,  of  course,  identical  with  the  other 
sugar  of  the  body.  If  there  be  any  advantage  in  protein  over  carbo- 
hydrate, it  must  lie  in  the  fraction  of  fatty  acids  from  which  sugar 
cannot  be  formed  and  which  are  burned  directly.  But  it  passes  imagina- 
tion to  ascribe  to  these  simple  fatty  acids  any  peculiar  and  particular 
functions  in  the  body.  So  far  as  we  know,  the  fatty  acid  fraction  of 
the  protein  is  worth  just  its  caloric  content  and  nothing  more.  The 
nitrogen  is  eliminated  as  urea  and  will  not  be  invoked  as  a  valuable 
substance.  When  one  contemplates  the  curves  in  the  elimination  of 
nitrogen  on  a  rich  protein  diet,  the  curve  of  production  of  heat  due 
to  the  specific  dynamic  action  of  the  protein  and  the  relatively  straight 
line  of  elimination  of  carbon  dioxid,  one  cannot  repel  the  feeling  that 
the  metabolism  of  exogenous  protein  is  a  wasteful  process. 

Has  the  use  of  protein  for  dynamogenetic  purposes  any  disadvantage  ? 
Chemically  and  calorically  it  is  an  undesirable  fuel.  Sugar  passes 
directly  from  the  mucous  membrane  of  the  intestine  for  utilization 
in  the  body.  The  products  of  the  digestion  of  protein  must  be  recon- 
structed. They  must  be  hydrolyzed,  the  amino-acids  deaminizated, 
and  the  nitrogenous  end  products  eliminated  by  the  kidneys.  This 
elimination  represents  work.  The  ideal  fuel  is  the  one  directly  avail- 
able for  combustion  without  preparation.  The  best  diet  theoretically 
is  the  one  that  makes  the  least  use  of  protein  as  a  fuel. 

Low  Protein  Diet. — Is  there  any  evidence  that  the  restriction  of 
protein  to  the  cellular  needs  carries  with  it  any  loss  of  vigor  to  the 
body,  any  restriction  of  function,  any  diminution  of  adaptation  and 
compensation  in  any  direction?    Mystical  references  to  such  supposed 


THE  NORMAL  DIET  499 

positive  properties  of  a  rich  protein  diet  are  not  absent  from  the  litera- 
ture; but  of  concrete  statement  there  is  none. 

Is  the  low  protein  diet  adapted  to  the  putting  on  of  flesh,  as  in  youth? 
This  is  a  point  commonly  misunderstood.  A  rich  protein  diet  is  not 
a  ration  that  makes  flesh.  A  pure  meat  diet  forms  very  little  flesh. 
The  protein  that  is  burned  as  fuel  makes  no  flesh.  The  protein  that 
is  ingested  in  excess  of  the  cellular  needs  is  catabolized,  it  is  not  con- 
verted into  flesh.  Stuffing  with  protein  does  not  lead  to  fleshening. 
It  is  carbohydrate  that  has  the  sparing  power  for  protein.  The  ideal 
ration  for  laying  on  muscle  is  a  moderate  input  of  protein  and  a  large 
ration  of  carbohydrate.  This  is  the  natural  relation  of  protein  to  fat 
and  carbohydrate  in  the  mother's  milk;  human  milk  contains  only 
about  0.3  to  0.5  gram  of  protein  per  kilo  per  day;  or  in  terms  of  calories, 
the  calories  of  the  protein  are  only  about  7  per  cent,  of  the  total  calories 
of  milk.  The  suckling  has  a  large  surface  area  and  a  high  coefficient 
of  heat  production,  but  the  protein  needs  are  no  more  than  those 
stated  in  the  figure  above.  It  is  the  heavy  ration  of  sugar  in  human 
milk  that  makes  the  low  protein  so  effective  as  a  flesh  builder,  and  this 
relation  holds  true  in  all  ages. 

Margin  of  Safety. — Does  the  figure  stated  furnish  a  wide  margin  for 
safety?  There  are,  of  course,  variations  in  the  unit  of  intensity  of 
metabolism.  As  a  rule,  the  protein  metabolism  will  be  roughly  pro- 
portional to  the  mass  of  protoplasm  in  the  body.  But  variations 
occur.  Diet  contains  always  more  or  less  preponderance  of  certain 
proteins;  this  is  not  to  be  avoided.  The  nitrogenous  balance  must 
always  be  considered  in  connection  with  the  total  heat  transformation. 
A  protein  minimum  must  not  represent  a  minimum  on  a  certain  diet. 
Total-N  must  not  be  held  synonymous  with  protein-N.  With  the 
use  of  certain  proteins,  wide  variations  would  be  observed;  in  direct 
experiments,  proteins  and  proteins  are  not  comparable.  The  lowest 
nitrogen  balance  on  a  single  ration  is  to  be  obtained  with  potatoes, 
rice  and  bread.  A  diet  of  peas  is  much  less  effective  in  attaining 
nitrogenous  equilibrium.  Thus  the  protein  minimum  of  a  single  food- 
stuff may  vary  50  to  even  80  per  cent.;  the  minimum  on  a  potato  diet 
is  scarcely  more  than  half  the  minimum  on  a  bread  diet.  Lower  still 
is  a  diet  of  casein  and  sugar.  Theoretically,  with  abundant  carbo- 
hydrate blood  serum  would  be  the  most  effective  protein  in  a  diet. 
These  observations  warn  us  that  the  arbitrary  establishment  of  a 
minimum  must  include  the  exact  conditions  of  the  test  or  experiment. 
The  standard  protein  minimum  must  also  be  so  ample  as  to  permit  of 
the  substitution  of  a  large  share  of  the  carbohydrate  by  fat,  at  the 
choice  of  the  individual.  Bearing  all  this  in  mind,  and  bearing  in  mind 
the  fact  that  a  minimum  diet  ration  must  in  every  instance  be  not  only 
safe  but  generous  when  it  is  allotted  to  a  multitude,  we  face  the  quantita- 
tive determination  of  the  margin  of  safety.  Certainly  100  per  cent, 
margin  of  safety  must  be  deemed  large  enough  to  cover  securely  and, 
indeed,  generously  every  possible  exigency.     This  would  make  the 


500  METABOLISM  CONSIDERED  AS  A   WHOLE 

protein  input  for  a  diet  of  mixed  proteins,  with  carbohydrates  and 
fats  in  the  proportion  of  choice,  about  1  gram  per  kilo  per  day  for  a 
subject  of  70  kilos.  For  a  smaller  subject,  the  ration  should  be  relatively 
a  little  larger;  for  a  larger  individual,  it  should  be  relatively  a  little 
smaller.  The  quantitative  relation  of  the  different  experimental  planes 
of  nitrogenous  metabolism,  including  this  figure  for  the  normal,  are 
grouped  in  the  following  table: 

Nitrogenous  metabolism  for  a  man  of  70  kilos  per  day: 

Catabolism  in  N-hunger  with  carbohydrates 10  to  15  grams 

Catabolism  in  starvation,  lowest  level 15  to  20  grams 

Nitrogenous   and   caloric   equilibrium,   with   ample  ingestion   of 

carbohydrate       .           ...      .      . 30  grams 

Nitrogenous  and  caloric  equilibrium,  largely  with  fat     ....  40  grams 

Normal  protein  input,  safety  margin  of  100  per  cent 70  grams 

Nitrogenous  and  caloric  equilibrium  on  protein  diet        ....  750  grams 

Plant  Protein. — Does  plant  protein  fill  the  requirements  of  a  diet 
as  well  as  animal  protein?  So  far  as  the  physiologist  is  concerned, 
the  question  of  vegetarianism  presents  no  difficulties.  Upon  minimal 
diets,  a  ration  of  vegetables  will  need  to  contain  more  protein  than  a 
mixed  diet,  simply  because  so  many  plant  proteins  are  one-sided  in 
their  content  of  amino-acids.  But  the  amino-acids  themselves  are 
identical  in  plant  and  animal  protein,  it  is  simply  a  question  of  all 
the  needed  amino-acids  being  present.  With  the  input  of  70  grams, 
plant  protein  is  fully  qualified  to  maintain  the  protein  metabolism. 
The  problem  of  availability  of  a  completely  vegetarian  diet  hinges 
upon  questions  of  bulk,  fermentability,  digestibility  and  variety — not 
upon  any  question  of  the  utilization  of  plant  proteins. 

Such  a  protein  input  is  certainly  sufficient  for  the  needs  of  the  body 
under  all  conditions  of  work  and  climatic  surroundings.  Work  and 
external  cold  demand  more  carbon,  and  while  this  may  be  furnished 
in  the  form  of  protein,  it  is  preferably  furnished  in  the  form  of  fat  or 
carbohydrate.  Granted  that  the  low  protein  diet  is  in  every  way 
equal  to  the  full  maintenance  of  the  body,  is  the  high  protein  diet 
to  be  condemned?  Does  the  extra  work  imposed  on  the  liver  and 
kidneys  constitute  an  overload  of  possible  danger?  In  health  this 
overload  seems  to  make  no  appreciable  difference,  it  is  well  within  the 
limit  of  adaptation  and  compensation.  But  in  many  subjects  the 
overload  is  not  well  tolerated.  And  although  in  modern  life  it  must 
be  recognized  that  the  carrying  of  overloads  is  necessary  in  our  com- 
plicated civilization,  it  is  hardly  to  be  considered  wise  for  one  to  deliber- 
ately elect  to  carry  an  overload  that  has  so  little  meaning  or  desirability. 
In  a  certain  sense,  a  heavy  meat  diet  is  to  be  classed  with  indulgence 
in  tobacco  and  alcohol;  in  moderation  of  no  demonstrable  injury  to 
perhaps  the  majority,  but  never  to  be  regarded  as  a  benefit. 

Intake  of  Carbohydrate  and  Fat. — The  relative  inputs  of  carbohydrate 
and  fat  depend  on  the  external  conditions  of  temperature,  on  work, 
on  the  digestion  of  the  subject  and  upon  taste.    For  moderate  caloric 


THE  NORMAL  DIET  501 

inputs  (up  to  3000  Calories  per  day)  carbohydrate  is  certainly  to  be 
preferred,  though  fat  should  not  be  excluded.  As  the  needs  for  heat 
rise,  the  input  of  fat  may  be  gradually  increased,  so  that  in  hard  physical 
work  it  is  well  to  have  fat  furnish  a  goodly  fraction  of  the  energy. 
There  is  a  certain  anti-sugar  fad  that  is  more  or  less  prevalent.  Accord- 
ing to  this  fad,  sugar  is  the  cause  of  many  ills,  very  loosely  defined. 
There  are,  of  course,  instances  in  which  starches  are  tolerated  in  the 
digestion  when  sugars  provoke  disturbance.  But  once  digested,  sugar 
and  starch  are  identical  in  chemical  and  physiological  properties. 
In  the  very  nature  of  industrialism,  carbohydrate  must  be  the  chief 
fuel  of  the  future,  since  animal  fat  is  produced  only  at  the  expense 
of  maintenance  of  a  costly  protein  metabolism.  Future  cultivation 
of  fat-bearing  plants  may,  however,  make  oils  partially  available  for 
nourishment  of  the  masses.  One  of  the  great  problems  of  the  future 
is  to  effect  reformation  of  customs  and  tastes  to  the  end  that  foods 
shall  be  cultivated  and  utilized  on  the  basis  of  caloric  value  per  unit 
of  price.  Domestic  management  in  this  country  is  grossly  extravagant 
because  of  ignorance  of  the  nutritional  values  of  foodstuffs  in  their 
native  and  prepared  states. 

Calculation  of  Diet  Values. — In  the  calculation  of  diet  values,  allow- 
ance must  be  made  for  the  unresorbed  fraction.  Taking  this  into 
account  with  normal  digestion,  it  is  approximately  correct  to  use  the 
following  constants  as  a  basis  for  calculations  applied  to  the  known 
amounts  in  the  diet.  The  figures  in  the  first  column  represent  the 
caloric  values,  in  the  second  column  are  the  caloric  values  in  utilization, 
per  gram. 

Actual  caloric  value  Caloric  value  in  diet 

Sugar 3.9\  4  0 

Starch 4.2/ 


Fat 9.4 9.0 

Protein  animal  .      .      .     4 .  4\  ^  q 

Protein  plant     .  4.2/ 


If  circumstances  compel  one  to  determine  the  unresorbed  residue, 
the  nitrogen  of  the  intestinal  secretions  must  be  taken  into  account, 
and  then  the  actual  values  for  protein  and  fat  can  be  used.  The  follow- 
ing table  gives  the  figures  for  a  number  of  arbitrary  normal  diets, 
ranged  for  progressively  greater  demands  for  heat,  the  amounts  being 
stated,  heat  in  calories,  foodstuffs  in  grams  per  day: 


Heat  requirements 

Calories 

Protein 

2100 

70 

3000 

70 

3500 

70 

4000 

70 

5000 

70 

6000 

70 

6000 

70 

Fat 

Carbohydrate 

50 

350 

75 

500 

100 

700 

150 

700 

225 

700 

250 

850 

400 

500 

502  METABOLISM  CONSIDERED  AS  A   WHOLE 

These  figures  represent  usual  averages  of  diets  of  choice  (with  protein 
fixed)  for  the  purposes  of  production  of  the  stated  amounts  of  heat, 
varying  from  the  state  of  rest  in  the  first  line  to  very  hard  manual 
work  in  the  last  line.  Usual  hard  work  does  not  require  over  4000 
Calories,  or  at  most  5000. 

The  figures  for  carbohydrate  and  fat  are  in  a  certain  sense  arbitrary, 
representing,  however,  usual  values.  Fat  and  carbohydrate  are  inter- 
changeable, within  certain  limits  in  the  diet,  in  accordance  with  the 
isodynamic  law,  which  holds  both  in  heat  production  and  in  work. 
The  restrictions  of  the  isodynamic  law  must  be  kept  in  mind.  This 
law  does  not  state  that  under  all  conditions  protein,  fat,  and  carbo- 
hydrate are  interchangeable  in  the  diet  in  the  proportions  of  their 
caloric  values.  For  protein  the  law  holds  only  for  the  dynamogenetic 
utilization  of  protein.  But  even  here  it  fails  with  large  ingestions, 
since  excessive  protein  input  results  in  an  exaggeration  in  the  total 
metabolism  and  heat  production,  which  an  isodynamic  ingestion  of 
sugar  or  fat  would  not  do.  Carbohydrates  should  be  replaced  by  fats 
only  above  the  limit  of  the  operation  of  the  saving  power  of  carbo- 
hydrate for  protein.  And  finally,  the  factor  of  digestion  may  complicate 
the  situation.  Nevertheless,  within  wide  limits  and  especially  for 
sugar  and  fat,  the  law  of  isodynamic  utilization  holds. 

NUTRITION   IN   INFANCY   AND   CHILDHOOD 

This  is  a  subject  of  great  importance  for  the  theory  as  well  as  for 
the  practice  of  nutrition.  Before  considering  the  metabolism  of  the 
child,  it  will  be  instructive  to  review  briefly  the  influence  of  gestation 
and  lactation  on  the  metabolism  of  the  mother. 

The  tissues  of  the  child  are  derived  from  the  mother  and  under  all 
circumstance,  therefore,  must  be  represented  in  her  metabolism.  But 
during  the  early  months  of  gestation,  the  growth  of  the  fetus  is  so 
gradual  and  involves  so  little  material,  that  any  effect  upon  the  metab- 
olism of  the  mother  could  not  be  marked.  On  the  other  hand,  the  preg- 
nant woman  is  building  uterine  tissue,  mammary  gland  substance,  and 
laying  on  flesh  herself,  largely  fat  it  is  true,  but  nevertheless  result- 
ing in  an  influence  on  the  total  metabolism.  A  retention  of  nitrogen 
would,  therefore,  be  expected  during  the  entire  period  of  gestation; 
during  the  early  months  largely  in  the  mother's  body,  during  the 
last  two  months  of  gestation,  however,  largely  in  the  body  of  the  child. 
Since  in  the  body  of  the  child  a  large  amount  of  special  proteins  are 
synthesized,  there  must  be  superfluous  amino-acids  to  be  catabolized. 
This  is  probably  the  cause  of  the  excess  of  nitrogen  to  be  found  in  the 
urine  of  animals  during  the  early  weeks  of  pregnancy,  increased  also 
by  the  superfluous  amino-acids  due  to  the  formation  of  uterine  tissue. 
At  the  same  time,  the  amount  of  excess  of  nitrogen  is  rather  more 
than  could  be  reasonably  accounted  for  on  this  basis  alone,  unless 
we  assume  that  the  processes  of  anabolism  in  the  early  establishment 


NUTRITION  IN  INFANCY  AND  CHILDHOOD  503 

of  the  central  tissues  are  particularly  specialized.  Later  a  retention 
of  nitrogen  is  observed,  and  corresponds  to  the  building  of  the  new 
tissues.  A  pregnant  female  will  retain  nitrogen  on  a  diet  that  pre- 
viously insured  only  equilibrium.  The  amount  of  retention  is  not 
large  until  the  final  weeks  of  gestation,  when  it  rises  rapidly  and  may 
during  the  last  days  reach  as  much  as  4  or  5  grams  of  nitrogen  per 
day.  After  delivery,  despite  the  establishment  of  the  secretion  of 
milk  (casein  formation),  the  nitrogen  of  the  urine  passes  from  retention 
to  loss,  on  account  of  involution  of  the  uterus  (a  self-digestion  that 
results  in  the  catabolism  of  a  large  mass  of  amino-acids),  extending 
over  a  number  of  days,  possibly  up  to  ten  days  or  two  weeks;  when 
involution  is  completed,  retention  for  purposes  of  casein  formation 
is  established.  It  is  doubtful  if  the  protein  formed  in  the  tissues  of 
the  full-term  child  exceeds  that  formed  in  the  gravid  uterus  and 
hypertrophied  breast  glands;  but  the  processes  are  very  specialized 
and  probably  require  more  substrate  protein. 

The  consumption  of  oxygen  and  the  elimination  of  carbon  dioxid 
at  the  close  of  pregnancy  will  run  from  20  to  40  per  cent,  above  the 
normal.  Not  all  of  this  is  to  be  attributed  to  the  fetus,  since  there  is 
extra  work  of  circulation  and  respiration;  and  the  additional  maternal 
tissues  have,  of  course,  their  metabolism.  In  the  study  of  pregnancy 
in  the  dog,  it  has  been  found  that  the  increased  heat  production  is 
proportional  to  the  number  of  young  in  the  litter. 

Lactation  is  a  process  involving  extensive  metabolic  functionation. 
The  milk  sugar  is  formed  in  the  mammary  gland  by  conversion  of 
d-glucose  into  d-galactose  and  the  union  of  these  to  form  the  disaccharid 
lactose.  The  fats  are  abstracted  from  the  body  fat  of  the  individual, 
and  vary  in  composition  with  the  body  fat;  no  synthetic  work  is  here 
done.  The  casein  must  be  formed  by  hydrolysis  of  the  blood  proteins 
within  the  epithelial  cells  of  the  gland,  followed  by  the  construction 
of  casein  from  the  amino-acids  thus  offered,  the  superfluous  amino- 
acids  being  burned.  The  work  of  lactation  is  much  greater  than  the 
work  of  gestation  in  the  unit  of  time;  100  c.c.  of  mother's  milk,  con- 
taining a  little  over  1  per  cent,  protein,  3  per  cent,  fat,  and  6  to  7  per 
cent,  sugar,  has  a  caloric  value  of  about  60  Calories.  A  usual  secretion 
during  the  first  weeks  of  lactation  will  run  as  high  as  400  c.c.  per  day 
with  a  caloric  value  of  some  250  Calories.  Later  in  lactation  when 
the  child  is  larger,  the  secretion  may  be  increased  to  equal  750  Calories 
per  day.  This  is  one-third  to  one-fourth  the  heat  production  of  the 
mother.  The  child  in  the  first  few  days  of  life  has  probably  three 
times  the  metabolism  that  it  had  in  the  uterus  during  the  last  days  of 
gestation.  It  is,  therefore,  clear  that  from  the  metabolic  standpoint, 
lactation  is  a  heavier  task  than  gestation. 

The  composition  of  milk  should  biologically  be  independent  of  the 
diet  of  the  mother.  As  a  matter  of  fact,  it  is  quite  independent.  Recent 
investigations  have  cast  much  doubt  upon  the  older  ideas  of  modifica- 
tion of  the  milk  by  modification  of  the  diet.     Starvation  makes  the 


504  METABOLISM  CONSIDERED  AS  A   WHOLE 

milk  rich  in  fat;  forced  feeding  with  carbohydrate  makes  the  milk 
poor  in  fat.  The  sugar  content  seems  quite  constant,  and  with  a  normal 
ration  of  protein,  the  casein  content  is  constant;  and  it  is  not  increased 
by  heavy  protein  diet.  The  amount  of  milk  is  quite  an  individual 
variable — just  as  in  cattle  it  is  a  variable  related  to  the  breed.  The 
milk  of  carnivora  is  very  concentrated,  that  of  herbivora  much  more 
diluted.  Peculiar  to  human  milk  is  the  low  content  of  protein  and  the 
high  content  of  sugar. 

Proportional  to  the  large  relative  area  of  surface  of  the  infant,  the 
per  kilo  metabolism  is  very  high.  For  each  kilogram  of  weight  in  the 
newborn  infant,  the  heat  production  is  about  100  Calories,  as  against 
30  for  the  adult.  The  heat  production  per  area  surface  is,  however, 
about  the  same,  from  1000  to  1200  Calories  per  square  meter  surface 
area  per  day.  Infants  are  normally  fairly  quiet  during  the  first  months 
of  life  and  as  they  are  kept  very  warm,  the  heat  production  of  muscular 
exercise  and  for  chemical  regulation  is  low.  Later,  of  course,  it  becomes 
large.  The  heat  production  per  kilogram  falls  as  the  child  grows, 
probably  in  a  curve  that  resembles  the  logarithmal  curve,  the  drop 
at  first  being  rapid,  later  more  and  more  gradual.  At  the  age  of  a  year 
the  total  metabolism  probably  corresponds  to  about  70  Calories  per 
kilo  per  day. 

Of  the  diet  necessary  to  maintain  this  high  intensity  of  metabolism, 
only  about  7  per  cent,  is  in  the  state  of  protein;  the  rest  is  divided 
between  sugar  and  fat  in  practically  equal  proportions.  A  normal 
growth  of  an  infant  corresponds  to  retention  of  from  12  to  20  per 
cent,  of  the  caloric  equivalent  of  the  total  metabolism.  In  other 
words,  if  a  child  produces  100  Calories  per  kilo,  the  diet  will  need  to 
contain  the  equal  of  from  112  to  120  Calories  per  kilo  per  day  at 
least.  The  retention  of  protein  amounts  to  from  25  to  40  per  cent,  of 
the  protein  input,  illustrating  the  extremely  advantageous  utilization 
of  a  small  ration  of  protein  when  ingested  with  an  abundance  of 
carbohydrate. 

The  same  law  of  growth  has  been  found  in  all  animals  tested.  Growth 
is  a  specific,  proportional  to  the  input  of  calories  in  the  milk,  the  heat 
production  of  exercise  being  taken  into  consideration.  From  this  it  is 
apparent  to  what  an  extent  the  daily  growth  of  an  infant  is  dependent 
upon  the  slight  excess  of  calories  in  the  food  over  calories  in  the  heat 
production;  a  very  little  may  make  or  mar  the  development  of  an 
infant.  The  rate  of  growth  for  man  is  very  slow  as  compared  with  the 
rate  of  growth  in  most  animals,  but  in  each  species  on  its  own  plane, 
the  law  holds.  In  growing  animals;  about  double  the  calories  of  the 
heat  production  are  contained  in  the  natural  diet;  about  35  per  cent, 
is  retained  as  growth,  the  rest  is  expended  in  muscular  exercise.  In 
the  case  of  infants  the  retention  for  growth,  which  is  a  specific  of  the 
species,  is  very  much  smaller  and  the  expenditure  also  much  lower, 
so  that  the  infant  does  not  ingest  food  containing  double  the  calories 
of  the  heat  production  of  the  day. 


CHRONIC  UNDERNUTRITION  505 

As  the  child  becomes  older  the  expenditure  for  muscular  movements 
increases,  while  the  ratio  of  growth  remains  about  the  same.  From 
infancy  to  adult  life,  the  daily  addition  to  the  body  weight  is  a  little 
more  than  proportional  to  the  body  weight.  A  disturbing  factor  is 
the  allowance  to  be  made  for  physical  exercise.  This  is  in  children 
often  displayed  to  the  point  of  exhaustion,  and  sometimes  makes 
the  heat  output  of  the  child  exceed  even  the  adult  output.  A  resting 
boy  of  ten  years,  should  have  a  metabolism  of  about  40  Calories  per 
kilo  per  day.  At  play,  the  diet  of  the  child  may  have  to  be  as  high  as 
100  Calories  per  kilo  per  day  to  maintain  caloric  equilibrium.  The 
diet  of  a  child  must,  therefore,  cover  the  basal  metabolism,  the  natural 
increment  of  growth  and  the  enormous  output  for  physical  exercise.  It 
is  the  inability  to  judge  these  fractions  correctly  that  is  responsible  for 
so  much  of  underfeeding  of  children.  There  are  furthermore  the  addi- 
tional deprivations  so  often  inflicted  on  children  by  the  application  of 
fad  notions  of  diet.  The  relative  caloric  input  of  a  normal  child  leading 
an  outdoor  life  is  to  be  compared  to  that  of  a  man  at  heaviest  physical 
work.  Protein  in  excess  is  not  needed,  that  is  clear;  but  total  calories 
are  needed,  in  the  form  of  sugar  and  fat.  Fat  is  especially  important 
in  the  diet  of  children,  though  it  need  never  exceed  one-fourth  or 
one-third  of  the  total  caloric  input. 


METABOLISM  IN   OLD    AGE 

Metabolism  in  old  age  is  relatively  comparable  to  that  in  adult  years 
under  similar  conditions  of  inactivity.  The  heat  production  per  kilo 
seems  to  be  lower,  a  couple  of  calories  per  kilo  per  day.  The  protein 
catabolism  is  low,  not  because  the  endogenous  protein  catabolism 
is  much  lower  than  at  earlier  years,  but  because  the  aged  consume 
usually  less  meat.  Less  than  0.6  gram  per  kilo  per  day  has  not  been 
recorded  for  the  protein  input  of  the  aged;  and  this  is  no  less  than  a 
normal  ration  when  the  depletion  of  the  tissues  is  taken  into  account, 
for  the  tissues  of  the  aged  are  richer  in  fat  and  poorer  in  protein  than 
in  earlier  life.  There  is  an  increased  adaptation  to  low  inputs  in  the 
diet,  probably  because  the  wear-and-tear  needs  are  low  under  the  con- 
ditions of  life.  In  a  certain  sense  metabolism  in  old  age  resembles  that 
in  chronic  subnutrition  of  mild  degree.  The  retention  of  protein  is 
least  of  all  possible  in  old  age;  and  corresponding  to  the  reduced  intensity 
of  protoplasmic  activity,  the  sparing  power  of  sugar  for  protein  is 
very  pronounced  in  old  age. 


CHRONIC   UNDERNUTRITION 

Under  conditions  of  want  or  associated  with  disease,  a  condition  of 
undernutrition  is  observed  that  is  as  interesting  physiologically  as  it 


506  METABOLISM  CONSIDERED  AS  A   WHOLE 

is  important  sociologically.  The  subject  subsists  on  diets  obviously 
below  normal  requirements,  often  for  long  periods  of  time  and  naturally 
with  marked  loss  of  flesh.  It  is  rare  that  the  condition  approaches 
starvation;  it  is  much  more  to  be  likened  to  protein  hunger,  since  under 
conditions  of  want  or  famine,  protein  is  the  food  most  lacking.  The 
nitrogen  of  such  subjects  may  remain  stationary  at  4  or  5  grams  per 
day.  There  is  nitrogenous  equilibrium.  When  the  protein  input  is 
raised  ever  so  little,  retention  of  nitrogen  is  observed;  it  is  apparent 
that  the  cells  have  been  depleted  and  on  opportunity  retain  protein 
for  restitution.  The  heat  production,  measured  by  the  consumption  of 
oxygen  and  the  elimination  of  carbon  dioxid,  is  usually  about  the  lowest 
normal  level,  28  Calories  per  kilo  per  day.  In  a  few  cases  the  heat 
production  has  been  calculated  to  be  as  low  as  24  Calories  per  kilo 
per  day.  The  very  lowest  values  are  to  be  seen  in  the  few  days  after 
the  defervescence  of  a  prolonged  and  severe  fever.  In  other  words, 
assuming  the  accuracy  of  the  observations,  these  subjects  may  present 
as  low  heat  production  as  the  lowest  values  of  normal  men  in  sleep  or 
at  complete  rest.  The  subjects  of  such  subnutrition  were  very  lethargic, 
and  doubtless  did  not  exert  themselves  much.  It  is  doubtful,  after 
allowance  is  made  for  muscular  activity,  if  the  heat  production  would 
fall  more  than  100  or  possibly  200  Calories  below  that  of  the  normal 
individual  of  low  caloric  output.  In  other  words,  the  adaptation  is 
largely  in  the  restriction  of  the  protein  catabolism  to  meet  a  very  low 
input,  rather  than  in  any  real  reduction  in  the  unit  of  heat  produc- 
tion or  total  metabolism.  If  the  ingestion  of  carbohydrates  be  raised, 
the  individual  will  retain  nitrogen  on  the  input  to  which  want  has 
accustomed  him.  The  total  heat  prodution  is  lower  because  the  total 
of  body  surface  shrinks  with  emaciation.  The  subjects  of  subnutrition 
not  the  result  of  disease  recover  on  diets  that  would  be  minimal  for 
normal  individuals,  and  later  display  the  usual  range  of  nitrogenous 
metabolism. 

OVERNUTRITION 

Overnutrition  means  fleshening  or  fattening,  or  both.  It  is  sometimes 
sought  by  the  physician,  but  is  more  often  a  natural  occurrence.  It 
is  of  importance  to  know  how  and  under  what  circumstances  flesh 
as  well  as  fat  can  be  deposited.  It  must  be  realized  in  the  first  place 
that  growth  is  not  completed  until  about  the  twenty-fourth  year; 
that  in  young  subjects  permanent  nitrogen  retention  (fleshening) 
is  rather  easily  accomplished.  There  is,  furthermore,  a  retention  due 
to  use.  If  a  person  be  worked  hard  and  persistently,  weight  will  be 
lost  but  muscle  will  be  gained;  there  will  be  retention  of  nitrogen, 
and  after  the  period  of  development  it  will  be  found  that  the  metab- 
olism per  kilo  body  weight  is  increased.  This  is  the  criterion  between 
fleshening  and  fattening.  Tested  under  conditions  of  perfect  rest, 
fleshening  raises  the  per  kilo  unit  of  metabolism,  fattening  lowers  it. 
The  reason  is  that  metabolism  is  a  function  of  protoplasm  not  of  fat; 


0VERNUTRIT10N  507 

in  fleshening  the  relative  proportion  of  protoplasm  in  the  body  is 
increased,  in  fattening  it  is  decreased;  when  the  total  metabolism  is 
reduced  to  the  kilo  weight  of  the  individual,  this  is  at  once  apparent. 

A  seasonal  variation  in  protein,  as  well  as  in  fat,  is  sometimes  to 
be  observed.  The  loss  of  weight  in  summer  and  gain  of  weight  in  winter 
may  be  in  part  a  loss  and  gain  in  flesh  as  well  as  in  fat.  Men  who 
have  returned  to  the  city  to  lead  a  life  of  leisure  after  a  strenuous 
summer,  are  liable,  in  the  gain  of  weight  that  occurs,  to  exhibit  for  a 
time  a  striking  permanent  retention  of  nitrogen. 

Forced  feeding  with  protein  in  the  presence  of  carbohydrate  has 
a  certain  retention  of  protein  as  a  result,  for  a  time  at  least.  Under 
usual  conditions,  the  retained  nitrogen  is  lost  after  the  forced  inges- 
tions of  protein  are  suspended,  especially  in  subjects  over  thirty  years 
of  age.  During  the  period  of  stuffing,  the  heat  production  of  the 
individual  exhibits  not  only  the  increase  due  to  the  specific  dynamic 
action  of  the  protein,  but  also  a  further  increase,  often  not  marked 
but  distinct.  This  is  usually  assumed  to  represent  the  metabolism 
of  the  extra-protoplasm  that  the  cells  take  on  under  forced  feeding. 
This  retention  may  be  in  the  circulating  fluids,  as  well  as  partly  in 
the  cells,  which  are  known  to  possess  a  power  of  physiological  enlarge- 
ment as  well  as  a  marked  faculty  of  attenuation  on  deprivation  of 
protein.  While  the  concentration  of  protein  in  the  blood  plasma  is 
not  materially  increased,  it  is  possible  that  the  total  mass  of  blood  in 
the  body  is  enlarged.  Analyses  of  flesh  of  animals  that  have  suffered 
forced  feeding  with  excess  of  protein  have  indicated  that  nitrogen  is 
held  in  non-protein  state,  yet  not  to  be  identified  with  the  extractive 
nitrogen.  Usually  this  retention  is  not  permanent;  if  into  cells,  later 
they  shrink  back  to  the  former  dimensions;  if  in  the  circulating  fluids, 
it  is  catabolized.  In  other  words,  in  the  absence  of  protoplasmic  under- 
nutrition, the  retention  of  nitrogen  accomplished  by  forced  feeding 
with  protein  is  not  permanent.  In  conditions  in  which  the  retention 
of  protein  is  permanent,  the  same  can  be  as  easily  accomplished  on  a 
moderate  protein  input  plus  liberal  carbohydrate. 

Fattening  cannot  occur  on  a  protein  diet.  Forced  feeding  with  fat 
in  excess  of  the  caloric  requirement  results  in  the  almost  quantitative 
deposition  of  the  fat  in  the  body.  This  is  unquestionably  the  most 
direct  and  effective  method  of  fattening,  if  the  organs  of  digestion 
tolerate  the  administration  of  such  amounts  of  fat.  When  carbo- 
hydrates are  ingested  in  excess  of  the  caloric  needs,  the  heat  produc- 
tion is  not  exaggerated;  but  yet  the  total  excess  of  carbohydrate  does 
not  seem  to  be  deposited  in  the  form  of  fat.  The  glycogen  stores  of 
the  body  are  under  these  circumstances  filled,  and  this  may  account 
in  part  for  the  discrepancy.  In  part,  the  discrepancy  may  be  due  to 
fermentation  of  carbohydrate  within  the  alimentary  tract.  While 
fattening  with  fat  is  experimentally  more  directly  effective  than 
fattening  with  carbohydrate,  little  difference  exists  practically  in 
the  utilization  of  the  two  rations. 


50$  METABOLISM  CONSIDERED  AS  A  WHOLE 


OBESITY 

It  is  a  common  observation  that  obesity  is  the  result  of  overindulgence 
in  food,  lack  of  exercise  or  both.  The  fact  that  the  tendency  to  obesity 
is  in  some  subjects  hereditary  and  very  pronounced,  has  led  to  the 
assumption  of  a  pathological  endogenous  form  of  obesity.  The  nature 
of  this  state  was  assumed  to  lie  in  a  retardation  or  reduction  in  the 
total  metabolism  or  in  a  suboxidation,  since  it  was  soon  learned  that 
the  protein  catabolism  was  normal.  The  possibility  of  such  a  sub- 
oxidation  has  been  elsewhere  discussed.  In  the  discussion  of  under- 
nutrition, it  was  pointed  out  that  the  unit  of  combustion  was  not  below 
the  lowest  normal  level.  The  same  statement  holds  true  for  obesity. 
Measured  by  the  consumption  of  oxygen  or  by  the  total  heat  pro- 
duction, the  results  are  within  normal  limits.  The  law  of  basal  heat 
production  remains  inviolable.  In  every  chemical  and  physical  way, 
the  subjects  of  obesity  spare  heat;  and  the  result  in  toto  is  a  very 
efficient  and  economical  organism.  The  obese  are  fat  not  because  they 
have  suboxidation  or  retarded  metabolism,  but  because  they  have  a 
very  effective  economy.  In  many  instances  of  obesity  the  heat  pro- 
duction is  not  low  but  high;  there  are  marked  differences  in  these 
individuals.  In  the  obese  with  high  heat  production,  this  will  be 
found  to  be  more  than  covered  by  very  high  input;  the  obese  with  low 
input  and  low  heat  production  remain  still  within  the  limits  of  normal 
variations. 


CHAPTER  X 

THE  PRODUCTION  OF  BODY  HEAT  AND  THE  REGULATION  OF 
BODY  TEMPERATURE 

In  the  cold-blooded  animals  the  velocity  of  chemical  reactions  is 
a  function  of  the  body  temperature.  If  we  chill  the  body  of  such  an 
animal,  the  chemical  reactions  of  the  metabolism  are  diminished;  if 
we  raise  the  body  temperature,  the  chemical  reactions  are  increased. 
These  animals  lack  all  mechanism  for  the  regulation  of  the  dissipation 
of  heat  produced  in  the  chemical  reactions  of  the  body.  The  body  of 
the  warm-blooded  animal  possesses  a  mechanism  for  the  regulation 
of  body  temperature.  If,  however,  the  body  temperature  is  raised 
above  the  normal,  the  same  law  that  holds  throughout  the  scale  for 
the  cold-blooded  animal  becomes  operative;  the  chemical  reactions 
are  increased  as  the  result  of  the  raising  of  the  body  temperature. 
In  cold-blooded  animals,  as  in  plants  and  bacteria,  there  is  a  mathe- 
matical expression  for  this  increase  in  chemical  reaction  as  the  result 
of  increase  in  temperature;  it  is  the  same  relation  known  to  exist  for 
chemical  systems  in  general,  namely,  that  for  each  10  degrees  increase 
in  temperature  (under  controlled  conditions),  the  velocity  of  the 
chemical  reaction  is  doubled  or  more  than  doubled.  If  we  could  reduce 
the  temperature  of  a  warm-blooded  animal  (which  the  chemical  regula- 
tion renders  impossible  so  long  as  function  remains)  it  would  be  found 
that  the  law  holds  also  for  warm-blooded  animals — just  as  it  has  been 
demonstrated  for  the  warm-blooded  cat  as  clearly  as  for  the  cold- 
blooded frog,  that  the  contractions  of  the  heart  are  a  function  of  tempera- 
ture. It  is  the  so-called  chemical  regulation  that  prevents  the  law 
of  dependence  of  reaction  velocity  on  temperature  being  demonstrable. 

There  are  four  separate  fractions  of  heat  production  in  the  animal 
body.  These  in  actual  life  overlap,  but  experimentally  they  may  be 
separated.  These  are:  the  basal,  irreducible  production  of  heat; 
the  heat  of  the  specific  dynamic  action  of  the  foodstuffs;  the  heat  of 
chemical  regulation;  and  the  heat  of  contraction  of  voluntary  muscles. 

Basal  Heat  Production. — The  basal  heat  production  represents  the 
heat  formed  in  the  fasting  animal,  at  complete  rest,  at  the  tempera- 
ture of  37°  C.  Of  this  heat  the  body  makes  no  use  under  these  cir- 
cumstances, since  the  body  temperature  would  be  maintained  by  the 
external  temperature.  As  a  matter  of  fact,  this  fraction  of  heat  produc- 
tion, under  modern  conditions  of  life  in  an  enclosed  room  with  appro- 
priate clothing,  is  the  same  at  33°  C.  The  amount  of  heat  herein  set 
free  is  not  a  strict  constant,  but  varies  in  different  individuals,  at 
different  ages,  in  the  two  sexes.  We  usually  express  heat  production 
in  terms  of  calories  per  kilo  per  day.      If  the  subject  be  in  normal 


510  BODY  HEAT  AND  BODY  TEMPERATURE 

flesh,  not  too  thin  and  not  too  fat,  this  approximate  mode  of  designa- 
tion is  satisfactory.  A  more  accurate  statement  for  most  purposes 
would  be  to  relate  the  heat  production  to  the  area  of  skin  surface. 
That  the  heat  of  chemical  regulation  is  directly  related  to  the  area 
of  skin,  under  conditions  of  temperature  lower  than  that  of  the  body, 
is  obvious;  that  the  basal  heat  production  at  body  temperature  is 
related  to  the  skin  area,  is  not  so  certain.  This  basal  heat  production 
we  may  view  as  the  expression  of  the  reaction  velocity  of  the  chemical 
system  of  the  body. 

The  amount  of  heat  set  free  in  this  fraction  is  easily  determined. 
It  varies  from  about  24  to  26  Calories  per  kilo  per  day,  or  for  a  body 
of  70  kilos,  approximately  from  1675  to  1800  Calories  per  day.  There 
are  some  individual  variations,  usually  in  the  upward  direction. 
Instances  have  been  known  in  which  by  indirect  calculation  it  seemed 
certain  that  the  basal  heat  output  could  not  be  over  1400  Calories 
per  day.  There  are  probably  individuals  in  whom  this  heat  production 
rises  to  2100  Calories  per  day.  It  is  difficult  to  be  definite,  for  the 
reason  that  experience  and  adaptation  on  the  part  of  the  subject  is 
required  to  enable  the  operator  to  exclude  all  heat  production  by 
muscular  movements.  But  on  the  whole,  25  Calories  per  kilo  per  day 
may  be  taken  as  a  general  average  and  few  exceptions  of  note  will 
be  found.  This  irreducible  basal  production  of  heat  continues  when 
none  is  needed  for  the  maintenance  of  the  body  temperature;  it  persists 
when  with  starvation  its  continuation  means  death.  The  body  can 
adapt  itself  to  needs  for  greater  heat  production;  it  has  no  adaptation 
to  lower  the  basal  heat  production.  This  may  be  accepted,  therefore, 
as  the  expression  of  the  reaction  velocity  of  the  chemical  system  of 
the  organized  body. 

In  this  heat  are  several  separable  fractions.  The  flow  of  circulation 
represents  work;  the  acts  of  respiration  represent  work.  There  is 
some  secretion  of  alimentary  juices,  even  in  fasting.  There  is  work 
expended  in  renal  elimination.  In  the  processes  of  cellular  repair  is 
chemical  work.  It  is  clear,  however,  that  these  all  do  not  make  up 
the  major  portion  of  this  heat  production.  The  largest  fraction  is 
undoubtedly  due  to  the  combustion  of  glucose  and  fat;  the  former, 
if  the  resting  fasting  body  be  well  stocked  with  glycogen;  the  later, 
in  the  event  of  prolonged  fasting. 

Heat  of  Specific  Dynamic  Action  of  Foodstuffs. — The  second  main 
fraction  of  heat  production  rests  upon  the  specific  dynamic  action  of 
the  foodstuffs.  This  has  been  discussed.  It  may  be  taken  to  represent 
200  to  300  Calories  per  day  on  average  mixed  diets,  lowest  when  the 
ration  of  protein  is  least. 

Heat  of  Chemical  Regulation. — The  third  fraction  is  derived  through 
reactions  of  combustion  aroused  through  chemical  regulation  of  body 
temperature.  When  in  a  resting  fasting  subject,  the  external  tempera- 
ture is  lowered  so  that  through  conduction  and  radiation  so  much  heat 
is  being  lost  that  the  body  temperature  cannot  be  held  constant  on 
the  heat  of  the  basal  production,  more  sugar  and  fat  are  cast  into  com- 


BODY  HEAT  AND  BODY  TEMPERATURE  511 

bustion  and  the  heat  production  brought  up  to  the  demands  of  the 
moment.  At  33°  C.  there  is  no  heat  production  of  chemical  regulation. 
It  appears  with  reduction  of  the  external  temperature  (or  in  any  way 
whereby  the  heat  dissipation  is  increased)  and  becomes  progressively 
greater  as  the  needs  increase.  How  much  heat  can  be  produced  in 
this  way  is  not  known,  as  it  is  very  difficult  to  exclude  muscular  exercise 
(shivering)  when  the  body  is  exposed.  This  function  may  be  cultivated, 
and  individuals  may  be  so  inured  to  external  cold  as  to  tolerate  with 
comfort  extreme  cold  for  long  periods  of  time.  This  is  especially  seen 
in  swimmers.  Any  figure  must  remain  a  conjecture,  but  possibly 
1000  Calories  of  heat  per  day  may  be  derived  from  the  heat  produc- 
tion aroused  through  chemical  regulation.  This  combustion  occurs 
largely  in  the  muscles,  associated  in  part  possibly  with  the  muscular 
tonus. 

Heat  Associated  with  Muscular  Contraction. — The  last  fraction  of 
heat  production  is  associated  with  muscular  contractions  of  the  skeletal 
system.  We  must  distinguish  between  three  kinds:  shivering,  in- 
voluntary restlessness,  and  motivated  movements.  Shivering  appears 
so  early  and  is  so  imperative  on  chilling  the  body  that  very  competent 
students  of  physiology  believe  that  chemical  regulation  consists  of 
shivering,  evident  or  hidden.  According  to  this  hypothesis,  being 
inured  to  cold  simply  means  technique  in  fibrillary  shivering.  It  is 
certain  that  this  is  incorrect.  Chemical  regulation  operates  through 
an  exaggeration  of  the  same  kind  of  combustion  of  carbonous  sub- 
stances that  evolves  the  larger  portion  of  the  basal  heat  production. 
Possibly  the  figure  allowed  for  heat  production  through  chemical 
regulation  is  far  too  high ;  but  heat  production  through  chemical  regula- 
tion is  certainly  not  heat  production  by  muscular  contractions.  Shiver- 
ing is  very  effective  in  the  production  of  heat,  though  on  prolonged 
exposure  to  cold  everyone  prefers  to  exercise  rather  than  shiver. 
Involuntary  movements  play  a  prominent  role  in  heat  production, 
and  are  the  bane  of  the  experimenter.  The  very  slight  muscular  differ- 
ence between  resting  seated  in  a  chair  and  resting  on  a  bed  may  lead 
to  an  increase  in  heat  production  of  no  less  than  20  per  cent.  The  fact 
of  training  in  the  technique  of  measurements  of  body  heat  on  the  part 
of  subjects  of  such  experiments  makes,  therefore,  the  greatest  difference 
in  the  results.  No  two  men  are  equally  still  when  lying  on  beds  as 
motionless  as  possible;  no  two  men  are  equally  still  when  asleep.  And 
no  two  men  are  equally  in  repose  under  any  stated  circumstance  of 
life.  The  marked  temperamental  differences  in  physical  restlessness 
we  term  "nervous"  and  "phlegmatic"  respectively.  It  is  this  element 
that  brings  the  heat  production  of  the  sedentary  man  from  the  basal 
production  of  possibly  1800  Calories  to  some  2500  or  more  Calories. 
To  this  must  be  added  the  heat  produced  through  motivated  move- 
ments, the  doing  of  work.  Work  may  be  classed  as  light,  medium, 
heavy  and  maximum.  Light  work  need  not  involve  the  output  of 
more  than  600  Calories  per  day;  moderate  work  will  involve  possibly 
the  production  of  as  much  more.    Heavy  work  may  involve  the  pro- 


512  BODY  HEAT  AND  BODY  TEMPERATURE 

duction  of  as  much  as  2000  Calories  per  day.  And  maximum  exertion, 
such  as  swimming  the  English  channel,  heavy  logging  or  participation 
in  a  six-day  bicycle  race,  may  involve  the  setting  free  of  as  much  as 
8000  additional  Calories  in  the  day.  It  is,  of  course,  only  exceptionally 
muscular  individuals  that  can  accomplish  such  performances.  The 
average  man,  even  in  training  for  the  particular  task,  can  probably 
not  work  hard  enough  to  produce  a  total  of  8000  Calories  of  heat 
(including  all  fractions)  in  the  twenty-four  hours.  The  relative  efficiency 
of  work,  as  related  to  the  associated  production  of  heat,  is  not  increased 
by  training;  but  the  numerical  possibilities  of  muscular  contractions 
of  a  given  type  are  enormously  increased  through  training.  Under 
normal  and  controlled  conditions,  all  these  forms  of  muscular  contrac- 
tions are  maintained  through  combustion  of  carbohydrate  and  fat 
largely;  the  protein  metabolism  need  not  be  increased  thereby,  nor  is 
muscular  wrork  of  ordinary  and  accustomed  type  followed  by  increase 
in  the  elimination  of  creatinin,  the  specific  product  of  muscular 
metabolism.  When  properly  lubricated,  the  running  machine  loses 
very  little  metal  from  its  working  parts;  and  the  muscle  looses  very 
little  creatin. 

The  following  table  presents  in  approximate  units  the  heat  outputs 
of  an  adult  under  the  usual  conditions  of  life  at  medium  activity  at  a 
temperature  of  15°. 

Warming  food  and  drink 50  Calories 

Warming  the  inspired  air 75 

Evaporation  of  water  from  lungs 250 

Heat  bound  in  carbon  dioxid 100 

Evaporation  from  skin 600 

Conduction  and  radiation  .      .  1300 

With  increased  work,  the  output  of  heat  by  radiation  and  conduction 
and  by  evaporation  of  water  from  the  skin  (to  a  slight  extent  also  from 
the  lungs)  will  be  divided  largely  according  to  the  individual  variable. 


THE  RELATION  OF  HEAT  PRODUCTION  TO  METABOLISM 

The  law  of  isodynamic  relation  of  foodstuffs  states  that  carbohydrate, 
fat  and  protein  may  replace  each  other  in  the  body  as  fuel  when  used 
in  the  proportions  of  their  caloric  values.  The  fixed  correlation  of  heat 
production  and  metabolism  rests  upon  this  basis.  If  in  the  resting, 
fasting  individual,  the  exact  amount  of  each  of  the  three  foodstuffs 
in  the  diet  be  known  and  the  outputs  of  carbon  and  nitrogen  be  known, 
the  heat  production  can  be  calculated  with  considerable  accuracy. 
Much  better  results  are  to  be  obtained,  however,  if  the  oxygen  absorp- 
tion, the  carbon  dioxid  output  and  the  nitrogen  output  are  known; 
from  these  three  data  the  heat  production  for  the  day  or  the  unit  of 
time  can  be  satisfactorily  computed.  It  is  also  possible  from  such  data 
to  calculate  back  to  the  foodstuffs  from  which  the  heat  must  have 
been  derived.  Recent  developments  in  the  direct  estimation  of  the 
body  heat  have  made  it  possible  to  compare  the  values  determined 


THE  RELATION  OF  HEAT  PRODUCTION  TO  METABOLISM     513 

by  the  use  of  the  respiration  apparatus  with  the  direct  measurement 
of  body  heat;  and  with  greatest  care  in  experimentation,  in  the  exact- 
ness of  analyses  and  in  the  control  of  the  subjects,  the  constants  have 
been  determined  with  such  precision  that  with  the  use  of  the  respira- 
tion apparatus  results  are  now  obtained  that  agree  very  well  with  the 
findings  by  direct  calorimetry.  Since  the  relative  amounts  of  carbon, 
hydrogen  and  oxygen  in  fat  and  sugar  are  not  identical,  the  relations 
of  heat  production  to  oxygen  comsumption  and  carbon  dioxid  elimina- 
tion must  vary.  In  other  words,  the  amount  of  heat  as  related  to  the 
oxygen  or  carbon  dioxid  is  different  in  the  combustions  of  fat  and  sugar, 
since  heat  is  formed  by  oxidation  of  both  hydrogen  and  carbon.  Fat 
is  almost  free  of  oxygen;  sugar  contains  enough  oxygen  to  combine 
with  all  the  hydrogen,  leaving  the  carbon  alone  to  require  oxygen. 
Therefore,  far  greater  amounts  of  oxygen  are  required  in  the  combus- 
tion of  fat  than  in  that  of  sugar,  and  this  is  strikingly  displayed  in  the 
respiratory  quotient.  The  same  argument  holds  for  protein,  though 
to  a  less  extent  than  for  fat.  The  caloric  equivalent  of  carbon  dioxid 
is  obtained  by  dividing  the  total  heat  production  in  Calories  by  the 
grams  of  carbon  dioxid  eliminated.  The  caloric  equivalent  of  oxygen 
is  obtained  by  dividing  the  total  heat  production  in  Calories  by  the 
grams  of  oxygen  absorbed.  The  caloric  value  of  the  protein  metabolism 
corresponds  to  about  26  Calories  for  each  gram  of  nitrogen  eliminated. 
The  caloric  equivalents  for  oxygen  and  carbon  dioxid,  together  with 
the  values  of  oxygen  for  each  gram  of  the  foodstuffs,  the  products  of 
oxidation  of  a  gram  of  the  same  and  the  respiratory  quotients  on 
combustion  of  each  foodstuff,  are  collected  in  the  following  table  taken 
from  Benedict  and  Joslin,  from  whom  are  also  taken  the  tables  that 
follow : 


Respiratory  quotients  and  caloric  equivalents  of  carbon  dioxid  and  oxygen 
for  protein,  fat,  and  carbohydrates. 


Oxygen  required 
to  oxidize  1  gram. 

Products  of  oxidation  of  1  gram. 

Respira- 
tory quo- 
tient. 

Caloric  equi- 
valent of 
1  gram. 

Foodstuff. 

Wgt. 
grms. 

Vol. 
c.c. 

C02 

*H20 

grms. 

Heat 
Cal. 

C02  c.c. 

of  C02 
pro- 
duced 
Cal. 

of 

Wgt. 
grms. 

Vol. 
c.c. 

oxy- 
gen re- 
quired 

Cal. 

O2  c.c. 

Starch  . 

1.185 

829.5 

1.629 

829.3 

0.556 

4.20 

1.000 

2.58 

3.55 

Cane  sugar 

1 .  122 

785.4 

1.543 

785.5 

0.579 

3.96 

1.000 

2.56 

3.53 

Glucose 

1.066 

746.2 

1.466 

746.2 

0.600 

3.75 

1.000 

2.56 

3.52 

Animal  fat 

2.876 

2013.2 

2.811 

1431.1 

1.065 

9.5 

0.711 

3.38 

3.30 

Human  fat 

2.844 

1990.8 

2.790 

1420.4 

1.055 

9.4 

1.713 

3.42 

3.36 

Protein 

1.367 

956.9 

1.520 

773.8 

0.340 

4.4 

0.809 

2.90 

3.22 

33 


514 


BODY  HEAT  AND  BODY  TEMPERATURE 


The  metabolism,  energy  transformation,  and  gaseous  exchange  is 
variable  from  individual  to  individual,  though  probably  a  constant  in 
the  same  individual  from  time  to  time.  The  variations  are  most  marked 
in  infancy  and  childhood,  but  are  evident  in  perfect  health  in  adult 
life.  This  is,  of  course,  what  we  should  expect,  since  the  intensity 
factor  of  protoplasm  is  a  variable.  As  a  rule,  the  smaller  the  body 
weight  the  larger  relatively  is  the  unit  of  transformation,  the  greater 
the  production  of  carbon  dioxid  and  consumption  of  oxygen.  There 
are  also  variations  between  the  tall  and  short,  the  lean  and  fat  of  the 
same  stature.  The  greatest  fluctuations  are  naturally  presented  in 
the  figures  for  output  of  carbon  dioxid.  In  the  comparison  of  the 
metabolism  of  one  individual  with  another,  sick  or  well,  these  differ- 
ences must  be  kept  in  mind.  And  variations  that  are  to  be  regarded 
as  abnormal  must  be  in  evidence  outside  the  known  ranges  of  normal 
variation.  The  following  tables  give  values  for  five  normal  subjects, 
and  give  a  fair  idea  of  the  range  of  variations  in  selected  individuals. 

Average  metabolism  of  normal  individuals  in  experiments  without 
food,  in  bed  calorimeter. 


Per  kilo  body  weight  per  minute. 

Heat  eliminated  per  kilo  body  weight 
per  hour. 

Subject. 

Body  weight. 

CO2  eliminated, 
c.c. 

Oxygen 

absorbed. 

c.c. 

Cal. 

(R.  Q.) 

1 

83.0    . 

2.76 

3.23 

1.01 

(0.854) 

2 

74.4 

2.77 

3.34 

0.95 

(0.800) 

3 

67.6 

2.86 

3.36 

0.96 

(0.851) 

4 

66.0 

2.94 

3.59 

1.00 

(0.819) 

5 

49.0 

3.43 

4.05 

1.13 

(0.846) 

Average 

.     2.95 

3.51 

1.01 

Apparently,  individual  and  normal  variations  up  to  15  per  cent,  may 
be  expected  in  the  measurement  of  the  total  metabolism  and  energy 
transformation  of  the  body. 

The  following  table  gives  the  figures  determined  with  the  same 
individuals  studied  in  the  recumbent  position  with  the  respiration 
apparatus.  Below  the  line  of  averages  are  the  figures  for  a  sixth 
subject,  who  displayed  rather  a  marked  individualism,  and  indicate 
what  must  be  expected  in  routine  examinations  of  this  kind. 


THE  RELATION  OF  HEAT  PRODUCTION  TO  METABOLISM     515 


Body  weight. 

Per  kilo  body  weight  per  minute. 

Subject. 

CO2  eliminated. 

Oxygen  absorbed. 

(R.  Q.) 

c.c. 

c.c. 

1 

82.0 

2.67 

3.30 

(0.810) 

2 

74.4 

2.67 

3.15 

(0.847) 

3 

66.0 

3.06 

3.68 

(0.831) 

4 

65.6 

2.87 

3.52 

(0.816) 

5 
Average 

49.0 

3.23 

.      .     2.90 

3.94 
3.52 
4.15 

(0.824) 

6 

59.0 

3.63 

(0.874) 

These  figures  emphasize  two  considerations.  The  variations  are 
usually  not  over  15  per  cent.,  but  a  subject  may  be  encountered,  as 
in  No.  6,  who  exhibits  a  more  decided  variation  from  the  average. 
The  results  with  the  respiration  apparatus,  the  subject  recumbent, 
are  so  closely  concordant  with  those  obtained  in  the  bed  calorimeter 
that  the  use  of  this  respiration  apparatus  (that  of  Benedict)  may  be 
safely  urged  upon  clinicians.  The  measurement  of  the  carbon  dioxid  is, 
as  a  measurement,  more  accurate  and  freer  of  liability  of  error  than  the 
measurement  of  the  oxygen.  But  the  value  of  the  figure  for  oxygen  is 
much  higher  for  the  purpose  of  calculation  of  total  energy  transforma- 
tion. In  diabetes,  where  little  carbohydrate  is  burned,  calculations 
on  the  basis  of  carbon  dioxid  elimination  give  very  good  results;  in 
these  cases  the  respiratory  quotient  will  indicate  the  state  of  the 
carbohydrate  combustion. 

Under  the  best  of  conditions  there  are  rather  large  opportunities 
for  error  in  the  interpretation  of  the  results  of  estimations  of  total 
energy  transformations.  This  is  due  largely  to  the  normal  variations, 
and  the  comparative  inability  of  the  experimenter  to  classify  the 
subject,  especially  under  conditions  of  disease.  Nevertheless,  with 
the  nitrogenous  metabolism  known  and  controlled  and  the  respiratory 
quotient  determined,  the  estimation  of  carbon  dioxid  output  and  oxygen 
intake  will  enable  us  to  calculate  closely  to  the  probably  total  heat 
production  of  the  body.  It  will  enable  one  at  least  to  determine  when 
this  is  notably  increased,  and  as  will  be  later  pointed  out,  the  matter 
of  decrease  demands  little  consideration.  A  diet  should  present  oppor- 
tunity for  caloric  as  well  as  nitrogenous  equilibrium;  and  unless  we 
wish  routinely  to  overfeed  carbon,  the  estimation  of  the  total  heat 
production  alone  will  enable  us  to  classify  diseases  on  the  basis  of  the 
total  transformation  of  energy  and  to  arrange  the  input  of  carbon 
accordingly. 


516  BODY  HEAT  AND  BODY  TEMPERATURE 

Importance  of  Respiratory  Quotient. — The  respiratory  quotient  has 
an  importance  beyond  that  of  its  use  in  the  calculation  of  total  heat 
production.  It  is  often  of  advantage  simply  to  know  in  what  state 
(fat  or  glucose)  the  carbon  of  the  body  is  being  burned.  Glucose 
requires  six  molecules  of  oxygen  to  convert  the  six  atoms  of  carbon 
into  carbon  dioxid;  the  hydrogen  requires  no  more  oxygen  than  the 
glucose  contains.  Fat  on  the  contrary  (we  are  concerned  with  the  fatty 
acid  alone)  using  stearic  acid  as  an  illustration,  contains  only  one  mole- 
cule of  oxygen  for  18  atoms  of  carbon  and  36  atoms  of  hydrogen.  To 
make  the  comparison  clear,  let  us  multiply  the  molecular  weight  of 
glucose  by  three,  or  in  other  words,  take  three  molecules  of  glucose 
which  has  the  same  amount  of  carbon  and  hydrogen  as  one  molecule 
of  stearic  acid. 


/ 


18H20  g02  in  C02         c»c.CO: 


3  C6H1206  +  I8O2   =  <  = =  Rq 

M8CO2  g02  c.c.02 

y18H20  go  in  C02        c.c.C02 

Ci8H3602  +  2602   =   <  = =  Rq 

M8CO2  g02  C.C.O2 

Since  the  respiratory  quotient  is  the  quotient  of  the  volume  of  carbon 
dioxid  over  the  volume  of  oxygen 

C02  c.c. 


02   c.c. 


it  is  clear  that  the  quotient  (1.0  in  the  case  of  sugar)  will  be  much 
lower  in  the  case  of  oxidation  of  fat,  about  0.7.  The  same  argument 
applies  to  the  combustion  of  protein,  except  that  on  account  of  the 
nitrogen  the  calculation  is  complicated.  Mixed  protein  may  be  calculated 
to  have  a  respiratory  quotient  on  combustion  of  about  0.8.  When  now 
the  nitrogenous  metabolism  is  known,  as  is  easily  to  be  determined  by 
the  knowledge  of  input  and  total  output,  the  respiratory  quotient  gives 
directly  a  good  indication  of  the  source  of  the  body  heat,  whether  from 
glucose  or  fat.  Making  now  allowance  for  the  nitrogenous  catabolism, 
we  can  use  a  table  of  interpolation  values  for  the  determination  of  the 
relative  degrees  of  combustion  of  fat  and  carbohydrate  in  a  body.  Such 
a  table  follows,  taken  from  Magnus-Levy. 


Respiratory- 

Caloric  value  per  L 

Division  of  fuel 

quotient 

oxygen 

Carbohydrate 

Fat 

1.000 

5.046 

100 

0 

0.950 

4.986 

83 

17 

0.900 

4.924 

66 

34 

0.850 

4.863 

49 

51 

0.800 

4.801 

32 

68 

0.750 

4.740 

15 

85 

0.707 

4.686 

0 

100 

The  values  for  each  25  in  the  scale  of  respiratory  quotients  can  be 
calculated  if  one  wishes  to  secure  greater  approximation.     By  the 


THE  REGULATION  OF  BODY  TEMPERATURE  517 

use  of  the  data  for  the  metabolism  of  nitrogen,  the  carbon  dioxid 
output  and  the  oxygen  consumption,  we  can  calculate  in  a  very  approxi- 
mate manner  the  total  heat  production  and  the  absolute  as  well  as 
relative  amounts  of  protein,  carbohydrate,  and  fat  that  have  been 
catabolized  in  the  body  during  the  period  of  the  experiment.  If  the 
normal  variations  were  less  and  if  we  could  properly  classify  a  sick 
subject  and  be  able  to  determine  his  norm  in  order  to  have  that  as  the 
basis  of  our  comparison  of  the  values  determined  under  conditions  of 
disease  (instead  of  being  compelled  to  compare  them  with  averages 
of  normal  values)  the  method  would  be  one  of  great  dependability 
for  bedside  work.  With  the  use  of  the  figure  for  oxygen,  instead  of 
that  for  carbon  dioxid,  as  the  basis  for  the  computation  of  the  heat,  the 
accuracy  of  the  calculation  is  much  increased;  so  much  so  that  the 
chief  error  in  the  application  of  the  method  to  the  study  of  the  sick  lies 
not  in  the  method  itself,  but  in  our  inability  to  form  an  accurate  notion 
of  the  normal  values  with  which  to  compare  the  findings  in  the  individual 
case  of  illness.  A  safe  rule,  with  the  respiratory  quotient  and  nitrogenous 
metabolism  known,  would  be  that  the  heat  values  calculated  by  the 
use  of  the  caloric  equivalents  of  carbon  dioxid  and  oxygen  must  display 
variation  of  notable  degree  and  in  the  same  direction.  The  absolute 
definition  of  the  amount  of  this  variation,  as  contrasted  with  normal 
averages,  must  then  rest  upon  the  value  for  total  energy  transforma- 
tion yielded  by  the  calculation  based  on  the  consumption  of  oxygen. 
In  all  investigations  of  this  character  it  is  essential  that  the  digestive 
organs  be  resting;  in  other  words,  the  tests  should  not  be  done  within 
at  least  fifteen  hours  of  the  taking  of  food,  and  a  longer  time  would 
be  more  certain.  The  best  plan  is  to  have  the  subject  eat  at  six  in  the 
evening;  and  then  without  breakfast  the  respiration  test  is  to  be  made 
the  following  morning  at  eleven  o'clock.  Such  a  postponement  of 
breakfast  can  nearly  always  be  tolerated  by  any  ordinarily  sick  subject 
without  ill  results.  A  prolongation  of  the  fast  for  a  few  hours  would 
give  greater  certainty  of  freedom  of  disturbance  by  digestion.  But 
in  an  individual  with  low  glycogen  stores,  even  such  a  short  fast  as 
twenty-four  hours  might  result  in  a  shift  to  the  combustion  of  fat 
greater  than  actually  normal  in  the  individual  at  the  time.  Such  a 
shortage  in  store  of  glycogen  would,  however,  in  itself  be  almost 
pathological.     Muscular  repose  is  imperative. 


THE  REGULATION  OF  BODY  TEMPERATURE 

Despite  the  fact  that  the  heat  evolved  in  the  four  named  fractions 
of  heat  production  vary  widely  in  the  diversified  circumstances  of 
life,  the  temperature  of  the  body  is  quite  constant.  It  is  obvious  that 
independently  of  heat  production,  the  body  of  the  warm-blooded 
animal  possesses  an  effective  mechanism  for  the  regulation  of  the 
several  factors  that  influence  the  temperature  of  the  body.     Under 


518  BODY  HEAT  AND  BODY  TEMPERATURE 

certain  circumstances  heat  must  be  conserved;  under  other  circum- 
stances heat  must  be  dissipated.  The  mechanism  for  the  regulation  of 
the  body  temperature  consists  in  the  co-adaptation  of  several  factors, 
operating  in  consonance  with  or  in  opposition  to  the  production  of 
heat.  These  factors  belong  either  to  chemical  regulation  or  to  physical 
regulation. 

Chemical  Regulation. — When  the  external  surface  of  the  body  is 
chilled,  increased  combustion  occurs  in  the  muscles  by  reflex  action; 
and  enough  more  heat,  within  reasonable  limits,  is  produced  to  main- 
tain the  body  temperature  despite  the  increased  dissipation.  This  is  the 
only  operation  of  chemical  regulation.  When  the  external  temperature 
is  above  30°  to  33°  C,  this  regulation  is  not  operative.  As  the  external 
temperature  is  lowered  and  the  dissipation  of  heat  from  the  skin  is 
increased,  more  heat  is  set  free  through  increased  combustion.  What 
amount  of  heat  may  be  produced  through  chemical  regulation  is  not 
known.  As  a  matter  of  fact  shivering  soon  sets  in,  which  indicates 
that  the  faculty  of  chemical  regulation  has  usually  a  limited  scope  of 
operation.  A  body  may  be  inured  to  exposure  to  cold  and  evidently 
there  is  adaptation  in  this  function.  The  heat  produced  through 
chemical  regulation,  when  it  is  operative,  is  directly  proportional  to 
the  distance  between  the  reading  of  the  thermometer  and  30°  C. — in 
the  absence  of  air  currents  and  of  unusual  humidity,  both  of  which 
exaggerate  the  radiation  of  heat  from  the  surface. 

As  previously  stated,  the  area  of  the  surface  of  the  body  is  a  funda- 
mental variable  to  which  the  production  of  heat  is  related;  in  other 
words,  the  heat  production  of  the  body  is  proportional  to  the  surface 
of  the  body.  This  law  of  skin  area  holds  very  closely.  The  surface 
area  of  an  animal  may  be  approximately  calculated  by  the  equation 
of  Meeh: 

S 
c  = 

S  and  W  being  surface  and  body  weight.  The  equation  in  use  is 
therefore,  S  =  CvW2.  The  constant  is  determined  empirically  by 
the  use  of  the  equation 


c  = 


w 


for  each  animal,  and  for  man  C  is  12.312.     The  formula  applied  is, 
therefore,  S  -  12.312i/W2. 

The  heat  production  of  the  resting  and  fasting  body  at  room  tem- 
perature, so  that  the  chemical  regulation  is  not  operative,  varies  from 
950  to  1200  Calories  per  square  meter  surface  area.  As  the  external 
temperature  is  lowered,  the  figure  is  progressively  increased.  The 
radiation  of  heat  is  proportional  to  the  area;  and  it  is  apparent  that  on 
external  cooling,  the  surface  area  determines  the  heat  production,  the 


THE  REGULATION  OF  BODY  TEMPERATURE  519 

body  temperature  being  kept  constant.  In  the  direct  sense  it  is  obvious 
that  the  basal  heat  production  is  related  to  the  surface  area  of  the  body. 
Two  men  of  dissimilar  size  with  a  lowered  external  temperature  produce 
heat  in  proportion  to  their  surface  areas.  Even  with  the  external 
temperature  above  the  body  temperature,  the  law  of  skin  area  holds, 
since  the  velocity  of  secretion  of  perspiration  for  evaporation  of  water 
is  proportional  to  the  surface  area,  other  things  being  equal.  Two 
men  of  dissimilar  size,  at  37°  produce  heat  in  proportion  to  their  areas, 
although  there  is  no  radiation.  It  is  important  to  know  whether  the 
relation  of  surface  area  to  body  weight  changes  with  states  of  flesh 
after  adult  dimensions  have  been  attained.  The  skin  is  very  imperfectly 
elastic,  and  with  loss  of  flesh  the  skin  assumes  a  more  or  less  wrinkled 
appearance,  especially  in  the  aged.  Nevertheless,  the  wrinkled  skin 
falls  into  folds,  so  that  the  actual  radiating  surface  area  is  not  as  large 
as  it  was  with  the  same  individual  when  the  wrinkled  skin  was  filled 
out  with  flesh.  If  the  heat  production  is  proportional  to  the  surface 
and  the  surface  area  in  elderly  wasted  people  is  increased  relatively 
to  the  body  weight,  then  we  should  obtain  high  values  for  the  relation 
of  heat  production  per  kilo  body  weight;  as  a  matter  of  fact  we  obtain 
rather  low  values.  The  same  applies  to  all  conditions  of  shrinkage  of 
body  weight,  and  thus  far  we  know  no  need  of  a  correction  on  account 
of  the  factor  of  loss  of  flesh.  The  relation  of  surface  area  to  weight  is 
much  larger  in  the  child  than  in  the  adult,  and  the  heat  production 
is  proportionately  larger. 

Physical  Regulation. — The  two  factors  in  the  physical  regulation  are 
conduction  and  radiation  of  heat,  and  perspiration  and  evaporation 
of  water.  The  body  loses  heat  in  small  part  by  warming  the  inspired  air 
and  the  food,  in  large  part  by  radiation  and  conduction  of  heat  from 
the  surface  and  by  perspiration  and  evaporation  of  water  from  lungs 
and  skin.  According  to  external  conditions,  the  body  employs  at  one 
time  largely  radiation  and  conduction,  at  another  time  perspiration 
and  evaporation — most  often  the  former. 

The  concrete  operation  of  the  physical  regulation  is  connected  with 
a  series  of  bodily  states  and  external  conditions.  These  are  as  follows: 
the  covering  of  hair  upon  the  skin;  the  thickness  of  the  skin;  the  blood 
supply  of  the  skin ;  the  fat  layer  beneath  the  skin ;  the  system  of  sweat 
glands;  the  exhalation  of  water;  the  external  temperature;  the  humidity 
of  the  atmosphere;  the  air  currents,  and  type  of  clothing.  While  the 
powers  of  adaptation  are  very  exceptional,  circumstances  arise  when 
it  is  not  possible  to  maintain  the  normal  body  temperature,  which  may 
be  lowered  or  raised  as  the  case  may  be. 

Hair. — The  covering  of  the  hair  upon  the  skin  is  of  very  little  impor- 
tance in  man,  as  the  hairy  covering  is  slight  and  is  in  any  event,  so  to 
speak,  included  in  the  clothing.  The  different  hairy  coats  of  different 
animals  explain  their  varying  resistance  to  cold;  cattle  will  freeze  to 
death  in  a  temperature  easily  tolerated  by  many  wild  animals.  Fur 
owes  its  protective  action  to  the  stationary  air  held  immovable  between 


520  BODY  HEAT  AND  BODY  TEMPERATURE 

the  hairs  (fur  consists  of  about  97  per  cent,  air  and  3  per  cent,  hair) ; 
the  hair  itself  is  a  poor  conductor  of  heat  and  the  immovable  air  is  a 
poor  conductor.  The  effectiveness  of  a  fur  depends  upon  the  degree 
to  which  the  hairs  imprison  the  air.  When  a  fur  is  wet,  the  hair  becomes 
a  good  conductor  of  heat  and  heat  is  abstracted  on  evaporation  of  the 
water.  The  presence  of  a  fatty  secretion  prevents  the  natural  fur  or 
feathers  from  becoming  really  wet,  the  water  is  shed  and  beneath  is 
the  same  layer  of  dry  stationary  air.  It  is  this  action  of  the  cutaneous 
lipoids  that  enables  animals  and  birds  to  remain  in  cold  water.  The 
clipping  of  a  fur  merely  means  reduction  in  the  layer  of  immovable  air, 
and  the  heat  dissipation  increases  accordingly.  The  heat  production 
of  birds  is  doubled  by  plucking  the  feathers.  Rabbits  that  have  been 
shaved  and  then  covered  with  starch  paste,  display  a  heat  production 
of  150  per  cent,  over  that  observed  in  the  native  state — simply  the 
increased  heat  production  to  meet  the  exaggerated  radiation  from  the 
depilated  skin.  In  the  spring  on  the  frontier,  the  boy  has  his  hair  cut 
and  the  sheep  are  sheared. 

The  effect  of  the  coat  of  hair  is  to  increase  the  range  of  external 
temperature  from  30°  downward  before  the  point  of  chemical  regulation 
is  reached.  The  heat  production  of  chemical  regulation  in  the  nude 
man  appears  when  the  external  temperature  is  lowered  below  33°  C. 
But  in  the  dog  this  does  not  appear  until  about  20°  C.  If  the  dog  be 
shaved,  chemical  regulation  will  become  operative  at  30°  C.  instead 
of  at  20°  C.  Man  by  his  habits  of  dress  attempts  to  surround  himself 
with  a  tropical  skin  temperature.  He  does  not  wish  to  employ  heat 
production  by  chemical  regulation;  but,  as  far  as  possible,  by  adapting 
his  manner  of  clothing  to  the  external  temperature,  extends  the  range 
of  physical  regulation  through  this  factor  of  cutaneous  protection. 
Practically  speaking,  apart  from  the  exposed  hands,  feet,  and  face,  the 
heat  lost  from  the  surface  of  the  skin  is  constant,  in  the  absence  of 
wind,  from  25°  to  possibly  near  zero,  through  adaptation  of  clothing. 
And  above  25°,  man  aims  in  the  other  direction,  by  reduction  of  cloth- 
ing, to  aid  heat  dissipation. 

Thickness  of  Skin. — The  thickness  of  the  skin  is  a  constant  under 
civilized  conditions,  apart  from  states  of  disease.  Barbarian  peoples 
who  have  inured  their  bare  bodies  to  external  temperature  have  the 
skin  thickened  by  exposure  and  friction,  as  in  the  case  of  the  hands 
and  feet  in  civilized  beings.  Not  an  inconsiderable  degree  of  protec- 
tion may  be  attained  in  this  thickening  of  the  horny  layer  of  the  skin. 
In  myxedema,  the  skin  is  thickened  by  the  deposition  of  an  abnormal 
substance  in  the  skin;  and  this  has  the  effect  of  reducing  the  unit  of 
radiation  of  heat  from  the  skin  of  these  subjects. 

Blood  Supply  of  Skin. — The  blood  supply  of  the  skin  is  a  most 
important  variable  in  man,  of  less  importance  in  the  fur-covered 
animals.  Restriction  of  heat  radiation  is  accomplished  by  constric- 
tion of  the  peripheral  vessels,  so  that  but  little  blood  courses  through 
the  skin  in  the  unit  of  time;  increase  in  heat  radiation  is  accomplished 


THE  REGULATION  OF  BODY  TEMPERATURE  521 

by  dilatation  of  the  peripheral  vessels,  so  that  much  blood  in  the  skin 
radiates  its  heat  outward.  The  function  of  perspiration  also  is  in  part 
a  function  of  the  variable  of  blood  supply;  dilated  capillaries  promote 
perspiration,  contracted  capillaries  depress  perspiration.  A  slight 
increase  in  the  interior  temperature  is  probably  the  moment  that 
reflexly  results  in  the  dilatation  of  the  peripheral  bloodvessels  and  so 
increases  the  radiation  of  heat  as  to  keep  the  blood  temperature  at 
the  normal.  The  flow  of  blood  to  the  skin  really  has  the  effect  of  rais- 
ing or  lowering  the  skin  temperature;  and  as  the  velocity  of  radiation 
of  heat  from  a  warm  to  a  cold  body  is  proportional  to  the  difference 
in  temperature,  the  result  is  obvious.  This  is  a  function  that  is  very 
variable  in  disease,  and  will  be  discussed  from  this  point  of  view  under 
fever.  Jt  is  probable  also  that  there  is  a  paralytic  dilatation  of  the 
peripheral  system  resulting  in  the  loss  of  this  function  of  regulation, 
with  the  effect  of  greatly  increasing  the  production  of  heat  at  all  but 
high  external  temperatures. 

The  Subcutaneous  Fat. — This  factor  operates  to  increase  the  range 
of  physical  regulation,  just  as  the  coat  of  fur  does.  The  protecting 
influence  is  proportional  to  the  thickness  of  the  layer  of  fat.  The 
layer  of  fat  operates  also  in  the  opposite  direction.  Vasomotor  dilata- 
tion is  less  effective  in  the  fat  individual  than  in  the  thin,  and  thus 
conduction  and  radiation  are  more  difficult.  A  current  of  air  at  35°  C. 
that  would  have  the  effect  of  cooling  a  thin  subject,  will  have  less 
effect  in  the  case  of  a  fat  subject.  The  cool  bath  and  shower  are  also 
less  effective.  Since  at  temperatures  up  to  that  of  the  body,  heat  is 
dissipated  by  conduction  and  radiation  as  well  as  by  evaporation,  the 
fat  man  with  the  restriction  of  conduction  and  radiation  is  thrown  more 
upon  evaporation  of  water,  which  explains  why  sweating  is  more  pro- 
nounced. When  now  with  high  humidity  the  evaporation  of  water  is 
made  difficult,  the  reason  for  the  especial  discomfort  of  the  fat  subject 
becomes  apparent.  The  exhaustion  commonly  associated  with  profuse 
perspiration  is,  of  course,  added  to  the  total  effect.  There  is,  however, 
a  further  fact,  since  the  two  factors  named  would  cease  to  distinguish 
the  fat  from  the  thin  subject  at  external  temperatures  equal  to  or 
above  that  of  the  body.  The  actual  heat  production  of  the  fat  subject 
seems  to  be  increased  more  than  in  the  case  of  a  thin  subject;  and  as 
evaporation  of  perspiration  alone  can  remove  the  heat,  the  stout  sub- 
ject is  at  a  disadvantage  as  compared  to  the  spare.  Just  how  the  in- 
creased heat  production  of  the  fat  subject  is  brought  about  in  advance 
of  increase  in  the  body  temperature,  is  not  clear. 

The  System  of  Sweat  Glands. — Dogs  and  cats  possess  no  sweat  glands 
in  the  skin,  and  must  remove  water  by  the  mouth.  In  man  the  system 
of  sweat  glands  is  by  no  means  a  constant,  but  varies  from  individual 
to  individual.  Not  a  few  persons  suffer  excessively  at  high  tempera- 
tures because  of  sparse  perspiration,  so  that  there  is  little  water  to 
evaporate.  An  occasional  individual  suffers  from  congenital  absence 
of  sweat  glands,  and  functional  inhibition  of  perspiration  sometimes 


522  BODY  HEAT  AND  BODY  TEMPERATURE 

occurs.  In  ichthyosis  hystrix  the  function  of  perspiration  is  abolished. 
When  the  subjects  of  this  disease  are  placed  in  a  warm  room,  the 
respirations  at  once  become  rapid  in  the  endeavor  to  eliminate  water, 
and  the  body  temperature  rises.  In  the  absence  of  the  function  of 
perspiration,  a  warm  atmosphere  has  the  same  effect  as  a  hot  bath 
of  the  same  temperature  on  a  normal  subject.  The  evaporation  of 
each  liter  of  water  abstracts  from  the  body  about  580  Calories;  and 
since  the  body  can  discharge  several  liters  of  perspiration  daily,  the 
individual  whose  function  of  sweating  is  naturally  or  pathologically 
reduced  is  at  a  serious  disadvantage  in  the  regulation  of  the  body  tem- 
perature. The  function  of  perspiration  is  normally  excited  by  high 
body  temperature  as  well  as  high  external  temperature,  as  indicated 
by  perspiration  during  work.  When  the  external  temperature  is 
lowered,  the  elimination  of  water  from  the  skin  falls  to  the  minimum  of 
insensible  perspiration.  The  skin  never  ceases  to  eliminate  water, 
and  500  grams  per  day  probably  represents  the  output  of  water  in 
ordinary  insensible  perspiration.  Obviously,  as  the  external  tempera- 
ture falls,  the  loss  of  body  heat  by  evaporation  becomes  less  and  less. 
A  resting  or  at  least  inactive  individual  with  a  total  heat  production 
of  3000  Calories  at  room  temperature,  will  lose  about  700  Calories 
by  evaporation  of  water,  and  of  this  about  450  Calories  are  lost  by 
evaporation  of  perspiration.  This  corresponds  to  some  750  grams  of 
water.  If  the  external  temperature  be  high,  this  may  rise  to  2  or  3 
liters,  even  at  rest  if  the  humidity  be  low.  At  hard  work  as  much  as 
5  to  7  liters  of  perspiration  may  be  eliminated;  if  the  temperature 
be  high  and  the  air  dry,  the  fraction  of  even  the  heaviest  perspiration 
that  evaporates  will  be  large;  if  the  humidity  be  high  this  is,  of  course, 
not  the  case.  As  air  currents  increase,  the  velocity  of  evaporation  as 
compared  with  that  in  a  still  atmosphere  is  augmented.  But  as  the 
influence  of  air  currents  on  conduction  and  radiation  is  still  more 
pronounced,  the  total  effect  is  to  reduce  perspiration  and  evaporation 
of  water.  Under  the  most  favorable  conditions,  three-fourths  of  the 
body  heat  may  be  dissipated  through  evaporation  of  perspiration; 
under  the  least  favorable  conditions  less  than  5  per  cent,  will  be  thus 
lost.  The  function  of  perspiration  and  the  variations  in  evaporation 
of  the  eliminated  water  are,  therefore,  of  extreme  importance  in  the 
mechanism  of  regulation  of  temperature. 

Exhalation  of  Water. — Since  the  air  of  the  breath  is  always  warmed 
to  the  temperature  of  the  body,  the  external  temperature  has  no  influ- 
ence on  the  water  content  of  the  expired  air,  which  is  normally  saturated 
with  moisture.  Under  usual  conditions  of  respiration,  about  400  grams 
of  water  will  be  eliminated  in  the  expired  air,  corresponding  to  a  loss 
of  heat  of  about  225  Calories.  Forced  respiration  will  raise  this  to 
about  600  grams  of  water,  corresponding  to  350  Calories  of  heat.  With 
very  rapid  respiration,  as  in  extreme  exercise,  ventilation  of  the  lungs 
is  no  longer  attended  with  saturation  of  the  expired  air  with  moisture. 
From  these  figures  it  is  clear  to  what  a  limited  extent  only  can  faulty 


THE  REGULATION  OF  BODY  TEMPERATURE  523 

cutaneous  elimination  of  water  be  compensated  for  by  increased  respira- 
tory activity.  The  elimination  of  water  from  the  lungs,  which  is  inde- 
pendent of  external  temperature,  is,  however,  inversely  proportional 
to  the  humidity;  and  this  fact,  under  the  usual  conditions  under  which 
a  compensation  for  cutaneous  elimination  would  be  desirable,  reduces 
the  faculty  of  adaptation  still  more. 

External  Temperature. — Since  the  velocity  of  conduction  and  radia- 
tion under  constant  conditions  is  proportional  to  the  difference  in  the 
temperature  between  the  body  and  the  external  medium,  the  lower 
the  external  temperature  the  greater  the  loss  of  heat.  Man  modifies 
this  factor  by  clothing  to  such  an  extent  as  practically  to  keep  his  body 
in  the  state  it  would  be  if  nude,  the  external  temperature  varied  only 
from  25°  to  37°  C.  In  animals,  of  course,  the  influence  is  of  predomin- 
ating importance.  A  dog  with  a  moderate  coat  of  hair  may  be  shown 
by  experiment  to  possess  physical  adaptation  to  external  temperature 
from  20°  to  30°  C;  on  being  shaved,  this  physical  adaptation  is  lost, 
and  the  heat  output  (and  necessarily  the  heat  production)  are  increased 
with  each  degree  of  temperature  lowered  from  30°.  And  yet  in  man  it 
can  be  shown  that  despite  clothing,  the  loss  of  heat  through  conduction 
and  radiation  may  vary  50  per  cent.  Since  customs  in  clothing  are 
determined  by  fashions  as  well  as  by  physics,  the  influence  of  external 
temperature  becomes  more  of  a  variable  under  modern  condition  of 
life  than  need  be.  Under  usual  conditions  of  living  probably  65  to  80 
per  cent,  of  the  body  heat  is  dissipated  by  conduction  and  radiation. 

Humidity  of  the  Atmosphere. — This  is  of  striking  influence,  since  it 
modifies  conduction  and  radiation  as  well  as  evaporation  of  water. 
At  medium  temperature  of  the  external  air,  say  at  18°  C,  the  influence 
of  humidity  is  slight.  As  the  temperature  is  lowered,  the  influence  of 
increasing  degrees  of  humidity  is  shown  in  increased  conduction  and 
radiation.  Since  with  lower  temperatures  there  is  little  perspiration, 
the  reduction  of  evaporation  by  increase  in  humidity  is  of  little  conse- 
quence. It  is  at  higher  temperatures  that  the  influence  of  humidity 
is  most  marked.  Here  there  is  little  conduction  and  radiation;  the 
dissipation  of  heat  is  accomplished  largely  by  evaporation  of  water, 
and  this  is  greatly  reduced  by  high  humidity.  A  dry  external  tempera- 
ture of  120°  F.  is  less  oppressive  at  Yuma  than  is  a  moist  external 
temperature  of  90°  F.  in  Philadelphia;  exertion  is  less  dangerous  and 
the  tendency  of  the  body  temperature  to  rise  less  pronounced. 

The  influence  of  the  bath  at  different  temperatures  is  dependent 
on  the  relations  to  conduction  and  radiation  on  the  one  hand,  and 
prevention  of  evaporation  of  water  on  the  other.  The  cold  bath, 
in  proportion  to  the  lowered  temperature  of  the  water,  abstracts  more 
and  more  heat  by  radiation,  so  that  if  the  body  temperature  is  to  be 
kept  up,  heat  production  must  be  stimulated  by  chemical  regulation 
and  by  shivering.  The  reduction  of  the  body  temperature  by  the  cold 
bath  is  based  upon  the  hypothesis  that  the  water  will  lower  the  febrile 
body  temperature  by  abstraction   of  heat  without  provoking  heat 


524  BODY  HEAT  AND  BODY  TEMPERATURE 

production  by  chemical  regulation  or  shivering.  As  a  matter  of  fact, 
in  practice  the  heat  is  abstracted  so  rapidly  that  chemical  regulation 
and  shivering  are  before  long  provoked;  but  the  loss  of  heat  is  greater 
than  the  increase  in  combustion,  so  that  the  end  result  is  a  lowering 
of  body  temperature.  Of  course,  if  the  water  is  cold  enough  and  the 
submergence  prolonged,  the  body  temperature  will  be  reduced  despite 
chemical  regulation  and  the  most  marked  muscular  movements.  This 
is  the  cause  of  failures  to  swim  the  British  channel;  the  loss  of  heat 
by  conduction  and  radiation  is  so  pronounced,  that  after  many  hours 
the  powers  of  heat  production  fail,  the  body  temperature  begins  to 
fall  and  the  swimmer  must  abandon  the  attempt.  Coating  of  the  skin 
with  vaselin  lowers  the  loss  of  heat;  but  even  under  the  best  of  condi- 
tions it  is  apparent  that  the  heat  production  in  the  twenty  and  more 
hours  that  the  swimmer  must  be  in  the  water  probably  exceeds  the 
largest  heat  productions  ever  measured,  10,000  Calories  per  day. 
The  few  men  who  have  accomplished  this  task  in  swimming  have 
probably  done  so  largely  on  account  of  unfavorable  conditions  for 
radiation,  such  as  thick  skin  and  subcutaneous  fat.  The  hot  bath 
checks  both  radiation  and  evaporation  of  water,  just  as  the  steam  room 
of  the  Turkish  bath;  and  as  the  dissipation  of  body  heat  is  so  restricted, 
the  body  temperature  rises  very  quickly.  The  influence  of  moisture 
alone  is  .well  realized  in  the  different  reactions  in  the  dry  hot,  and 
moist  hot  rooms  of  the  Turkish  bath;  the  dry  room  is  tolerable  at 
very  high  temperature,  the  steam  room  is  soon  intolerable  at  a  tem- 
perature very  little  above  that  of  the  body. 

Air  Currents. — The  influence  of  air  currents  is  to  intensify  conduc- 
tion and  radiation  and  evaporation  of  water.  The  lower  the  tempera- 
ture the  more  marked  the  first  of  these  results.  With  a  fixed  air  current, 
increase  in  humidity  results  in  increasing  conduction  and  radiation 
with  falling  temperature.  At  high  temperature,  high  humidity  reduces 
the  evaporation  of  perspiration  by  an  air  current.  A  wind  of  a  certain 
velocity  has  little  influence  on  a  moist  hot  day  on  the  Atlantic  seaboard ; 
a  wind  of  the  same  velocity  at  the  same  temperature  will  necessitate 
the  use  of  a  wrap  in  southern  California.  A  still  cold  carries  little 
danger  for  stock  on  the  western  plains;  the  same  cold  with  strong  wind 
means  the  death  of  stock  by  freezing.  A  wind  of  a  velocity  of  a  half 
meter  per  second  is  perceptible;  and  even  so  slight  an  air  current  will 
have  a  marked  influence  on  conduction,  radiation,  and  evaporation  of 
water  as  compared  with  the  results  in  a  still  atmosphere.  In  a  still 
atmosphere,  the  body  has  about  it  a  zone  of  warmed  air,  slowly  rising, 
but  acting  in  a  sense  as  a  blanket,  since  it  is  almost  stationary;  air 
currents  serve  to  continue  the  maximum  difference  between  external 
and  skin  temperatures.  A  slight  wind  can  easily  raise  the  heat  dissipa- 
tion, and  consequently  the  heat  production,  to  a  goodly  extent,  as  shown 
in  the  following  figures  taken  from  Wolpert: 


THE  REGULATION  OF  BODY  TEMPERATURE  525 


CO2  output  per  hour 

CO2  output  per  hour  with 

Temperature 

calm 

wind  8  M.  per  second 

10  to  15° 

25.1 

30.0 

15  to  20° 

24.1 

30.0 

20  to  25° 

25.0 

28.0 

25  to  30° 

25.3 

24.4 

30  to  35° 

23.7 

21.6 

The  subject  wore  usual  summer  clothes,  yet  the  effect  was  marked. 
Under  modern  conditions  of  life,  we  attempt  to  obviate  or  utilize  the 
influence  of  air  currents  by  adaptation  of  dress.  We  permit  access  of 
air  currents  to  the  skin  when  at  high  temperature  evaporation  of  water 
is  desired;  we  exclude  air  currents  when  at  low  temperature  con- 
duction and  radiation  would  be  exaggerated.  The  dictates  of  fashion 
frequently  lead  to  disregard  of  physical  regulation.  Women  wear 
summer  garments  in  winter.  When  one  reviews  the  data  relating  to 
the  production  of  carbon  dioxid  at  fixed  temperatures  with  varying 
weights  of  clothing,  and  then  contemplates  the  present  flimsiness  and 
scantiness  of  women's  apparel  and  the  exposure  of  children's  arms  and 
legs  at  low  external  temperature,  one  will  realize  that  at  least  a  goodly 
caloric  price  must  be  paid. 

Type  of  Clothing. — Fiber,  weave  and  weight  modify  the  physical 
properties  of  clothing  and  permit  the  reasonable  individual  to  adapt 
this  covering  to  the  exigencies  of  nature  and  the  laws  of  physics.  With 
a  fixed  fiber,  a  dense  weave  excludes  air  currents,  lowering  conduction 
and  radiation  in  cold  weather  and  lowering  evaporation  in  warm 
weather.  Dense  weaves  absorb  water  poorly,  a  matter  of  little  impor- 
tance with  the  slight  perspiration  at  low  external  temperature,  but 
of  great  importance  in  warm  weather,  since  ready  absorption  means 
rapid  evaporation.  A  loose  weave  permits  of  free  ventilation,  chilling 
in  winter  but  affording  in  summer  rapid  absorption  of  perspiration 
and  evaporation  of  the  water.  Variations  in  fiber  are  of  less  conse- 
quence than  variations  in  weave;  and  variously  current  opinions  on 
this  and  that  fiber  are  largely  arbitrary,  though  as  a  rule,  animal  fibers 
absorb  water  less  rapidly  than  plant  fibers,  even  when  the  weave  is 
identical.  This  suggests  plant  fiber  for  clothing  next  to  the  skin  and 
animal  fiber  for  external  clothing,  at  least  under  conditions  when 
conscious  perspiration  is  likely  to  occur.  Fads  dominate  clothing  to 
the  partial  exclusion  of  hygiene.  The  reasonable  individual  will  follow 
the  golden  path  between  forced  inurement  to  the  elements  and  complete 
protection  from  the  elements. 

The  result  of  the  co-operation  of  the  forces  of  heat  production  and 
heat  dissipation,  under  the  control  of  the  heat  centre,  is  that  with 
few  exceptions  the  body  temperature  is  maintained  fairly  constant, 
even  under  very  different  conditions.  There  is  a  diurnal  variation  of 
a  half  of  a  degree  or  so,  largely  individual.  The  mean  of  body  tempera- 
ture in  different  individuals  may  vary  a  degree.  It  is  clear  that  even 
on  the  basal  heat  production,  the  body  temperature  could  rise  above 
the  normal  if  the  adaptations  for  the  regulation  of  the  dissipation  of 


526  BODY  HEAT  AND  BODY   TEMPERATURE 

heat  were  disturbed.  On  the  other  hand,  it  is  clear  that  with  increased 
heat  production,  the  body  temperature  could  fall  if  the  adaptation  for 
the  regulation  of  heat  dissipation  were  disorganized.  When  the  condi- 
tions for  the  production  of  heat  are  unfavorable  and  those  for  the  loss 
of  heat  favorable,  body  temperature  may  fall.  When  the  conditions 
for  heat  production  are  favorable  and  those  for  heat  dissipation  are 
unfavorable,  body  temperature  must  rise.  The  phenomenon  of  fever, 
therefore,  to  which  we  must  next  turn  our  attention,  cannot  be  regarded 
as  a  constant  effect  of  a  constant  cause.  Abnormal  lowering  of  body 
temperature  is  uncommon;  fever  is  very  common.  In  shock  there 
is  subnormal  temperature,  as  there  are  in  some  very  grave  infections 
and  intoxications.  These  are  all  probably  due  to  serious  reduction  in 
heat  production  aided  by  excessive  heat  dissipation.  But  we  have 
no  reliable  analytical  data  on  this  question.  Investigations  of  the 
important  question  of  shock  have  not  followed  the  direction  of  the 
measurement  of  heat  production  and  heat  dissipation  under  constant 
conditions,  which  indeed  in  the  very  nature  of  the  circumstances  of 
shock,  infection,  coma  and  intoxication  are  difficult  if  not  impossible 
of  realization. 

FEVER 

When  one  considers  the  frequent  occurrence  of  fever,  the  paucity 
of  our  information  relative  to  the  production  of  heat  and  the  regula- 
tion of  temperature  in  clinical  conditions  of  fever  is  amazing.  In  truth, 
however,  the  reason  has  been  in  part,  due  to  methods.  Until  very 
recently  the  methods  of  indirect  calorimetry  have  been  cumbersome 
and  also  inexact.  The  use  of  the  respiration-chamber  type  of  calori- 
meter has  been  out  of  the  question.  Added  to  this  was  the  impossibility, 
and  often  undesirability,  of  placing  the  patient  under  the  strict  control 
of  diet  that  would  be  required  in  an  exact  metabolic  and  calorimetric 
experiment.  The  recent  improvements  and  simplification  of  the  respira- 
tion apparatus  in  the  Carnegie  Nutrition  Laboratory,  and  the  more 
accurate  definition  of  caloric  coefficients,  have  now  placed  it  within 
the  power  of  every  well-equipped  hospital  to  conduct  investigations 
into  the  metabolism  of  patients  afflicted  with  infectious  and  other 
febrile  diseases.  The  literature  on  fever  is  enormous,  and  in  part 
filled  with  contradictions  in  matters  of  fact  as  well  as  divergencies  in 
point  of  view.  An  exhaustive  discussion  of  the  subject  of  fever  cannot 
be  here  undertaken.  But  it  is  possible  within  the  space  here  available 
to  correlate  the  known  facts  of  fever  with  the  known  facts  of  the  physi- 
ology of  heat  production  and  temperature  regulation.  It  will  be  best 
to  discuss  the  matter  under  specific  headings. 

Under  what  conditions  does  fever  appear  in  the  normal  body?  We 
know  of  two  physiological  or  experimental  forms  of  fever;  the  fact 
that  fever  of  these  types  may  exist  naturally  does  not  make  the  designa- 
tions improper.    When  the  body  is  placed  in  a  bath  at  40°  C,  the  body 


FEVER  527 

temperature  must  rise  because  with  loss  of  heat  through  radiation  and 
evaporation  excluded,  the  continuance  of  the  basal  heat  production 
necessarily  raises  the  temperature  of  the  body.  The  various  forms  of 
heat  stroke  represent  this  type  of  fever  in  nature.  When  a  puncture 
is  made  in  the  corpora  striata,  the  temperature  rises  promptly.  If  the 
liver  be  freed  of  glycogen  before  the  puncture  is  done,  no  fever  is  pro- 
voked. In  some  way,  therefore,  the  puncture  has  caused  a  sudden, 
almost  explosive  combustion  of  the  glycogen  in  the  liver.  No  gluco- 
suria  appears.  This  combustion  is  shown  to  occur  in  the  liver  by  the 
fact  that  the  temperature  of  the  liver  and  blood  under  these  circum- 
stances becomes  higher  than  the  temperature  in  the  muscles;  whereas 
normally  it  is  in  the  muscles,  where  the  usual  combustion  of  glucose 
occurs,  that  the  temperature  is  highest.  Just  how  large  is  the  increase 
in  heat  production  is  not  known.  It  is  assumed,  quite  without  experi- 
mental reasons,  that  the  sudden  excess  of  production  of  heat  is  so 
pronounced  that  the  full  normal  mechanism  for  the  dissipation  of  heat 
is  impotent  to  cope  with  it  for  a  time;  and  as  a  result  of  excess  of  heat 
production  transcending  the  powers  of  heat  dissipation,  the  body 
temperature  rises.  It  is  possible  that  the  sudden  high  fever  sometimes 
seen  in  injury  of  the  base  of  the  brain,  and  also  in  lesions  of  this  region, 
may  be  due  to  irritation  or  injury  of  the  so-called  heat-puncture 'Centre. 

When  all  the  other  instances  and  forms  of  fevers  are  analyzed,  it 
seems  possible  to  place  them  in  one  of  two  groups:  (a)  Fever  due  to 
disintegration  within  the  body  of  tissue  separated  from  its  nutrition, 
tissues  in  aseptic  necrosis,  (b)  Fever  due  to  the  presence  and  functiona- 
tion  of  microorganisms,  bacteria  or  protozoa.  The  number  of  instances 
of  the  first  type  of  fever  is  small,  the  last-named  form  comprises  practi- 
cally all  the  clinical  states  of  fever.  In  all,  the  causation  of  the  fever 
is  to  be  related  to  chemical  substances  elaborated  in  these  cells,  bacteria 
or  protozoa,  or  formed  in  association  with  their  life  or  death  within  the 
body. 

Production  of  Heat  in  Fever. — Since  the  production  of  heat  is  primary 
and  the  dissipation  of  heat  secondary,  investigation  naturally  approaches 
the  former  first.  Is  there  increase  of  heat  production  in  fever?  In 
many  instances  of  fever,  yes;  in  some  fevers  there  is  no  increase  in  heat 
production.  The  latter  must  be  due  solely  to  derangement  in  regula- 
tion. In  the  instances  in  which  there  is  increase  in  heat  production, 
is  there  also  increase  in  nitrogenous  catabolism?  Does  the  increase 
in  nitrogenous  catabolism  account  fully  for  the  increase  in  heat  pro- 
duction, or  is  there  increase  in  combustion  of  glucose  and  fat?  In 
normal  individuals,  would  the  amount  of  heat  concerned  in  the  increase 
in  heat  production  observed  in  febrile  disease  lead  to  increase  in  body 
temperature,  is  it  such  an  amount  of  heat  as  to  tax  the  mechanism  of 
regulation  of  body  temperature?  Does  such  a  degree  of  increase  in  the 
nitrogenous  catabolism  under  all  circumstances  lead  to  fever?  Have 
we  knowledge  of  a  febrile  exaggeration  in  nitrogenous  catabolism? 
These  questions  we  will  consider  seriatim. 


528  BODY  HEAT  AND  BODY  TEMPERATURE 

There  is  increase  in  heat  production  in  many  cases  of  fever.  When 
the  data  are  analyzed,  it  becomes  clear  that,  as  a  rule,  there  is  little 
increase  in  heat  production  in  fever  of  usual  degree,  up  to  39°  C; 
but  that  in  high  fever  and  apparently  proportional  to  the  fever,  the 
production  of  heat  is  increased.  It  is  quite  certain  that  we  deal  with 
two  increases  in  heat  production,  of  different  origination.  In  the  one, 
the  increase  in  heat  production  is  primary;  whether  it  be  the  cause 
of  the  fever  or  not,  it  is  associated  with  the  infectious  or  toxic  condition 
that  is  at  the  basis  of  the  disease.  In  the  second,  the  increase  in  heat 
production  is  secondary  to  the  fever  itself;  it  is  the  expression  of  the 
increased  velocity  of  reactions  in  the  body  at  higher  temperature. 
When  the  body  temperature  of  a  normal  subject  is  raised  by  lying  in 
a  hot  bath,  the  heat  production  is  increased  also,  purely  as  a  result 
of  the  increased  body  temperature.  It  makes  no  difference  what  may 
be  the  cause  of  the  fever;  fever  itself,  in  accordance  with  the  general 
law  of  chemical  reaction  velocity,  leads  to  increase  in  reaction  velocity 
in  the  organism,  to  increased  heat  production.  This  should  effect  both 
the  catabolism  of  protein  and  the  burning  of  carbohydrate.  These 
two  elements  of  increase  in  heat  production  doubtless  overlap.  The 
first  is  a  constant,  presumably  of  the  infective  process,  but  may  be 
exaggerated  by  higher  body  temperature.  The  second  does  not  become 
measurable  at  slightly  febrile  temperature,  but  increases  progressively 
as  the  body  temperature  rises.  Obviously  these  two  increments  of 
increase  in  body  heat  only  add  to  the  problem  of  heat  dissipation. 

The  amounts  of  heat  involved  in  the  increased  production  are  difficult 
to  define,  since  they  are  usually  determined  by  calculation  of  the  carbon 
dioxid,  and  the  diet  and  other  conditions  cannot  be  controlled.  By 
interpolation  and  the  use  of  data  obtained  on  animals,  it  seems  certain 
that  the  amount  of  extra  heat  will  not  usually  exceed  a  few  hundred 
Calories;  it  is  doubtful  if  the  extra  heat  production  in  a  febrile  disease 
in  man  ever  reaches  a  1000  Calories  a  day  over  the  normal  output 
of  the  individual  under  identical  conditions.  Experimental  infections 
in  animals  have  yielded  increase  in  heat  production  of  as  high  as  50 
per  cent.  (6  to  7  per  cent,  increase  for  each  degree  C.  fever) ;  and  this 
marked  increase  is  covered  by  the  allowance  of  a  1000  Calories.  The 
resting  subject  of  70  kilos  (in  the  sense  of  rest  as  a  febrile  subject  would 
rest)  on  light  diet  would  develop  about  30  Calories  per  kilo  per  day, 
or  2100  for  the  total.  An  increase  to  45  Calories  per  kilo  per  day  with 
a  fever  would  be  very  unusual;  but  even  then  the  total  would  be  only 
3200  Calories. 

The  increase  in  heat  production  is  not  a  unit;  in  it  are  included  in 
different  cases  and  under  different  circumstances,  at  least  four  frac- 
tions of  heat.  One  is  due  to  toxic  exaggeration  of  protein  catabolism. 
A  second  is  due  to  exaggerated  catabolism  due  to  depletion  of  glycogen. 
The  patients  in  the  first  few  days  of  fever  do  not  eat,  the  combustions 
deplete  the  glycogen  (demonstrably  low  in  the  tissues  in  febrile  infec- 
tions) and  under  these  circumstances  the  subject  presents  the  combus- 


FEVER  529 

tion  of  the  first  few  days  of  starvation,  protein  catabolism  high  on 
account  of  lack  of  glycogen.  A  third,  present  in  some  cases,  is  due  to 
muscular  contractions,  the  shivering  in  the  state  of  chill  in  such  infec- 
tions as  are  attended  with  chills.  The  end  capillaries  are  forcibly  con- 
stricted, the  skin  becomes  cold  and  shivering  sets  in,  as  always,  when 
the  skin  is  chilled.  Lastly,  we  have  the  fraction  of  heat  due  to  the  excess 
of  catabolism  caused  by  the  higher  temperature  of  the  body. 

Is  there  increase  in  nitrogenous  catabolism?  In  many  cases  there  is 
increase  in  the  catabolism  of  common  protein,  in  many  cases  increase 
in  purin,  and  in  some  cases  possibly  in  creatinin.  The  loss  in  nitrogen 
(in  uncontrolled  cases  it  must  be  conceded)  may  be  as  high  as  10  grams 
per  day  above  the  normal.  Usually  it  is  under  5  grams.  In  some 
cases  of  febrile  infection  it  is  not  demonstrable.  The  cases  with  high 
fever,  other  things  being  equal,  tend  to  have  the  highest  catabolism 
of  protein. 

Increase  in  Protein  Catabolism. — This  exaggeration  of  protein  catabo- 
lism is  in  part  of  toxic  origin,  the  direct  result  of  the  action  of  bacterial 
products  on  the  cells,  especially  of  the  muscles  and  glands.  The  in- 
crease in  protein  catabolism  may  antedate  the  onset  of  fever.  The 
hyaline  degeneration  of  muscle  cells  seen  in  some  fevers  suggests  itself 
as  the  morphological  counterpart  of  the  toxic  action  of  the  bacterial 
products,  of  which  the  increased  catabolism  is  the  chemical  result; 
fatty  degeneration  in  the  liver  cells  is  another  evidence.  Yet  it  is 
surprising  how  slight  this  exaggeration  of  protein  catabolism  may  be 
when  the  diet  of  the  subjects  of  infectious  fevers  is  probably  controlled. 
Many  cases  of  fever  suffer  from  glycogen  hunger,  with  the  attending 
increase  in  the  catabolism  of  protein,  due  to  absence  of  the  saving 
power  of  carbohydrate.  The  subject  of  an  infectious  fever  has  not 
lost  the  power  of  sparing  protein  with  glucose;  and  by  the  administra- 
tion of  large  rations  of  sugar,  the  nitrogen  output  may  often  be  held 
to  the  normal.  This  is  not  true  of  all  infections,  however,  but  it  is 
a  very  important  fact  in  the  treatment  of  fever. 

In  high  fever  the  heavy  increase  in  protein  catabolism  is  to  a  goodly 
extent  due  simply  to  increase  in  the  reaction  velocity  as  the  result 
of  increased  temperature.  A  bath  of  40°  C.  will  cause  as  much  increase 
in  nitrogenous  catabolism  in  the  unit  of  time  as  is  to  be  seen  in  many 
cases  of  fever.  Under  these  circumstances,  with  an  adequate  input  of 
carbohydrate,  the  more  marked  the  excess  of  protein  catabolism  at 
lower  degrees  of  fever,  the  more  certain  we  are  that  it  is  a  toxic  result; 
the  more  dependent  the  excess  on  the  height  of  body  temperature,  the 
more  likely  it  is  that  it  is  due  to  hyperthermia  rather  than  to  specific 
intoxication.  The  amounts  of  catabolism  of  protein  that  are  involved 
are  usually  not  large;  20  per  cent,  above  the  normal  with  body  tempera- 
ture under  40°  C,  may  be  an  average.  Increases  up  to  50  per  cent, 
have,  however,  been  observed.  Usually  it  is  easily  possible  to  establish 
a  nitrogenous  equilibrium.  In  some  severe  cases,  however,  this  does 
not  seem  possible,  even  with  liberal  rations  of  carbohydrate;  the  out- 
34 


530  BODY  HEAT  AND  BODY  TEMPERATURE 

put  remains  above  the  input,  no  matter  how  the  input  is  advanced. 
It  must  be  confessed,  however,  that  in  the  state  of  disturbed  diges- 
tion and  with  the  lack  of  control  that  seems  almost  a  humane  necessity 
in  dealing  with  these  subjects,  the  tests  are  not  entirely  convincing. 

Does  the  increase  in  the  catabolism  of  protein  account  fully  for 
the  increase  in  heat  production,  or  is  there  increase  in  the  combustion 
of  sugar  and  fat?  In  some  cases  the  mere  heat  of  the  specific  dynamic 
action  of  the  protein  catabolized  is  enough  to  account  for  the  increase 
in  heat  observed.  When  the  ingestion  of  carbohydrate  is  adequate,  the 
heat  production  will  sometimes  be  found  greater  than  is  to  be  accounted 
for  by  the  catabolism  of  protein,  assuming  that  this  is  accurately 
represented  by  the  output  of  nitrogen.  In  infections,  typhoid  fever 
especially,  there  is  sometimes  a  post-febrile  diuresis  in  which  large 
amounts  of  nitrogenous  substances  are  eliminated  that  have  apparently 
accumulated  in  the  body;  and  when  these  are  taken  into  account,  what 
seemed  to  be  a  balance  for  the  period  of  fever  is  converted  into  a  deficit. 
Daily  observations  are,  therefore,  not  enough.  But  apparently  there 
are  many  cases  in  which  the  excess  of  nitrogen  in  the  urine  is  not  as 
large  as  the  excess  of  heat  production.  In  experimental  work  on  animals, 
the  fat  combustion  has  also  been  found  increased,  though  there  is  a 
general  idea  that  in  man  the  combustion  of  fat  is  not  increased  in  fever 
except  with  underfeeding  with  carbohydrate.  It  is,  however,  believed 
that  overcombustion  of  glucose  often  occurs,  even  with  adequate  feeding 
of  carbohydrate  and  protein. 

Do  such  increases  in  the  catabolism  of  protein  as  are  to  be  observed 
in  even  the  most  extreme  cases  lead  per  se  to  fever?  This  question 
must  receive  a  decided  answer  in  the  negative.  It  is  possible  to  obtain 
increase  in  heat  production  through  exaggeration  of  protein  catabolism 
far  in  excess  of  any  ever  observed  in  human  or  experimental  fever, 
without  the  slightest  rise  in  body  temperature. 

Inadequate  Dissipation  of  Heat. — In  the  normal  body,  wrould  the 
amount  of  heat  concerned  in  the  increase  in  heat  production  observed 
in  fevers  lead  to  elevation  of  body  temperature?  Certainly  not.  When 
one  recalls  the  ease  with  which  under  the  external  conditions  that 
surround  the  sick  subject,  the  normal  mechanism  for  the  regulation 
of  body  temperature  is  able  to  dissipate  4000  to  6000  Calories  in  the 
day,  the  failure  of  the  febrile  individual  cannot  be  ascribed  to  over- 
production of  heat,  to  an  excess  of  heat  production  taxing  the  normal 
powers  of  heat  dissipation.  All  the  data  lead  to  the  conclusion  that 
the  cause  of  fever  is  not  abnormal  production  of  heat.  At  the  most, 
such  abnormal  production  of  heat  as  has  been  recorded  in  the  subjects 
of  fever  could  only  constitute  an  increment,  and  usually  a  small  one. 
The  cause  of  the  fever  lies  in  failure  of  adequate  and  regulated  dissipa- 
tion of  heat. 

This  statement  is  capable  of  direct  demonstration  in  animals.  When 
rabbits  are  injected  with  pyogenic  microorganisms,  it  can  be  shown 
that  during  the  period  of  oncoming  fever,  the  actual  dissipation  of 


FEVER  531 

heat  falls  to  about  95  per  cent,  of  that  of  the  controls.  If  under  these 
circumstances  the  heat  production  had  been  only  normal,  this  differ- 
ence must  have  led  to  fever  within  a  few  hours.  With  this  fact  estab- 
lished, two  questions  arise.  Wherein  lies  the  defect  in  heat  dissipa- 
tion, represented  in  the  5  per  cent,  in  rabbits?  When  heat  production 
and  heat  dissipation  are  in  equilibrium  at  the  higher  level,  what  condi- 
tions in  the  mechanism  of  regulation  operate  to  hold  the  level  above 
the  normal? 

The  defect  may  lie  in  restriction  of  the  functions'  of  conduction 
and  radiation  of  heat  from  the  skin.  The  defect  may  lie  in  suppression 
of  perspiration  and  of  evaporation  from  the  skin.  None  of  the  minor 
avenues  of  heat  dissipation  can  enter  into  account.  There  is  no  such 
thing,  with  quiet  respiration,  as  reduction  in  the  volume  of  water 
discharged  in  the  exhaled  air.  There  is  evidence  that  both  conduction- 
radiation  and  perspiration-evaporation  are  in  part  crippled  in  fever. 
It  is  only  a  question  of  diminished  adaptation;  lost  these  functions  are 
not,  as  will  be  seen.  Be  the  heat  production  normal,  increased  or  even 
subnormal,  the  functions  of  dissipation  do  not  operate  to  maintain  the 
equilibrium  at  the  normal  level. 

Perspiration  and  Evaporation. — An  adult  subject,  at  rest  in  bed  at 
ordinary  room  temperature,  may  eliminate  by  perspiration  about 
500  to  600  grams  of  water.  Let  it  be  assumed  that  heat  production 
and  loss  of  heat  by  conduction  and  radiation  are  constant.  A  toxic 
agent  operates  to  reduce  the  perspiration  of  water  one-half;  and  as 
this  reduces  heat  dissipation  by  175  Calories,  unless  another  avenue 
of  heat  dissipation  is  able  to  assume  the  extra  burden,  the  heat 
remains  in  the  body.  Now  175  Calories  represent  raising  the  tem- 
perature of  70  kilos  of  water  (the  weight  of  the  adult  body)  about 
2i°  C.  And  the  regular  reduction  of  the  function  of  perspiration 
to  the  extent  named,  unless  compensated  for  by  another  avenue  of 
heat  dissipation,  would  maintain  an  adult  body  in  fever.  There  is 
usually  a  close  connection  between  the  function  of  cutaneous  circula- 
tion, which  is  the  chief  factor  in  conduction  and  radiation,  and  that  of 
perspiration.  And  the  toxic  agent  that  would  operate  to  depress 
perspiration  would  tend  to  reduce  cutaneous  circulation.  Thus  the 
heat  retained  in  the  body  by  lack  of  the  normal  evaporation  of  perspira- 
tion would  not  be  removed  by  radiation.  If  not  removed  by  increased 
expiration,  which  would  hardly  be  possible,  fever  would  inevitably 
result.  In  ichthyosis  hystrix  the  function  of  conduction  and  radiation 
is  very  impotent  between  30°  and  37°,  the  slightest  alteration  in  room 
temperature  between  these  two  points  is  reflected  in  the  body  tem- 
perature. And  we  may  be  sure  that  this  represents  about  the  normal 
situation  in  the  function  of  conduction  and  radiation.  Under  the 
ordinary  conditions  of  life,  therefore,  a  marked  reduction  in  the  func- 
tion of  insensible  perspiration  would  probably  lead  to  fever.  At  low 
external  temperature  this,  factor  would  not  alone  be  effective.  But 
as  a  rule,  with  heated  houses  and  clothing,  we  keep  our  bodies  within 


532  BODY  HEAT  AND  BODY  TEMPERATURE 

the  range  of  temperature  where  the  function  of  water  evaporation  is 
a  very  important  fraction  of  the  heat  dissipation.  And,  furthermore, 
the  two  functions  are  inclined  to  act  together  and  defect  in  one  is 
fairly  certain  to  be  associated  with  defect  in  the  other. 

Is  fever  associated  with  reduction  in  perspiration  and  evaporation 
from  the  skin?  In  rabbits  the  ratio  of  heat  lost  by  evaporation  of 
water  and  by  conduction  and  radiation  is  constant  in  normal  and 
febrile  animals.  The  direct  experimental  demonstration  that  the 
normal  plane  of  insensible  perspiration  is  lowered  in  fever,  has  not 
been  accomplished.  It  is  demonstrable,  however,  that  the  faculty  of 
increase  in  the  evaporation  of  water  is  limited  in  fever.  The  evapora- 
tion of  water  is  subnormal  during  the  rise  of  fever,  but  at  the  height 
of  fever  is  identical  with  the  evaporation  at  normal  temperature.  The 
usual  increase  of  perspiration  after  the  ingestion  of  food  is  less  marked 
in  the  febrile  state.  A  normal  subject  whose  temperature  is  raised 
by  staying  in  the  steam  room  of  the  Turkish  bath  will  give  off  much 
more  sweat  than  will  be  eliminated  by  the  febrile  subject  with  the 
same  body  temperature.  Apparently,  therefore,  in  fever  a  positive 
reduction  of  the  normal  degree  of  perspiration  need  not  occur;  but  the 
normal  faculty  of  free  perspiration  at  higher  temperature  is  lost  or 
greatly  restricted.  In  the  fevers  of  sudden  rise  with  chill,  it  seems 
certain  that  the  insensible  perspiration  is  reduced  during  the  period 
of  rise  of  the  fever. 

Reduced  Conduction  and  Radiation  of  Heat. — The  direct  demonstra- 
tion of  reduced  conduction  and  radiation  of  heat  from  the  skin  has 
not  been  accomplished  experimentally  in  a  satisfactory  manner.  There 
is  no  question  that  during  the  period  of  rise  of  fever  the  skin  is  cold; 
the  vasomotor  constrictor  influences  are  operative  and  the  skin  is 
quite  bloodless.  The  temperature  of  the  skin  remains  below  what 
it  would  be  normally  under  the  same  circumstances  of  external  tem- 
perature, especially  in  the  extremities.  The  phenomena  that  attend 
the  cold  bath  are  evidently  reversed  in  fever.  The  action  of  cold 
water  is  at  first  to  cause  a  peripheral  vasomotor  constriction,  which 
drives  the  blood  from  the  skin  and  leads  to  a  rapid  rise  of  temperature; 
this  is  reduced  by  the  loss  of  heat  in  the  skin  that  attends  the  glow 
of  the  reaction.  In  fever  the  impulse  for  vasoconstriction  proceeds 
from  the  inside,  and  is  continuous.  The  fact  that  glow  and  warmth  of 
skin  as  well  as  perspiration  attend  the  defervescence  of  fever,  suggests 
strongly  that  the  opposite  states  belong  to  the  rise  of  fever.  When 
one  realizes  that  an  increase  of  heat  corresponding  to  but  a  tenth  of 
the  daily  normal  basal  heat  production  is  enough  to  maintain  a  moderate 
fever,  it  is  apparent  that  fever  might  be  induced  by  slight  inhibition 
of  the  two  chief  functions  of  heat  dissipation.  Investigations  into  the 
so-called  neurogenetic  fevers  have  indicated  that  here  the  heat  produc- 
tion is  either  normal  or  subnormal;  the  defect  lies  solely  in  the  disturb- 
ance of  the  mechanism  of  dissipation. 

At  the  point  where  the  febrile  body  temperature  is,  for  the  time 


FEVER  533 

being,  stationary,  the  heat  production  and  dissipation  are  equal.  This 
is  easily  explained.  The  radiation  of  heat  from  a  warm  to  a  cold  body 
is  proportional  to  the  difference  in  their  temperatures.  When  the 
body  temperature  is  raised  above  the  normal,  with  fixed  external 
temperature,  the  distance  between  the  temperature  of  the  body  and 
the  external  temperature  is  increased;  and  of  course  the  velocity  of 
radiation  from  the  warm  body  is  increased.  A  point  will  be  reached 
when,  despite  lowered  conduction  through  restriction  of  circulation, 
the  heat  radiation  will  equal  the  heat  production.  It  is  in  fever  just 
as  though  one  were  to  insert  a  fourth  lining  in  a  three-walled  ther- 
mostat. With  fixed  external  temperature  and  constant  heating,  the 
temperature  of  the  thermostat  would  rise  until  the  velocity  of  heat 
radiation  under  the  conditions  of  the  fourth  lining  equals  the  heat 
production.  The  situation  is  in  a  sense  the  converse  of  that  which  occurs 
when  the  hibernating  animal  holes  in.  The  heat  production  falls; 
the  body  temperature  will,  therefore,  fall  until  the  radiation  at  the 
new  plane  of  production  equals  the  production — when  the  body  tem- 
perature remains  constant  during  the  winter  sleep. 

The  relation  of  the  surface  of  radiation  to  the  development  of  fever 
explains  the  great  liability  of  children  to  fever.  The  surface  of  the  child, 
as  contrasted  with  the  mass  of  metabolic  tissue,  is  very  large.  Disturb- 
ances in  the  functions  of  radiation  from  this  large  surface  must  dispropor- 
tionately influence  the  body  temperature,  when  contrasted  with  the  rela- 
tions in  adults.  Just  as  the  child  chills  very  easily,  so  must  the  child 
fever  easily. 

Pathological  variations  in  the  functions  of  conduction  and  radiation 
occur  in  the  opposite  direction,  and  in  perspiration  also.  There  are 
vasomotor  derangements  in  which  constant  sensible  and  even  profuse 
sweating  occurs  at  room  temperature.  Evaporation  of  this  water 
must  lead  to  a  marked  increase  in  heat  dissipation,  and  must  necessitate 
a  corresponding  increase  in  heat  production.  In  exophthalmic  goitre, 
in  the  severe  stages  at  least,  the  peripheral  bloodvessels  are  widely 
dilated,  the  circulation  of  the  skin  is  very  free  and  the  dissipation  of 
heat  by  conduction  and  radiation  is  very  marked.  The  heat  produc- 
tion of  the  subject  is  also  very  high.  Which  is  primary — heat  production 
or  heat  dissipation — and  which  secondary,  is  not  known  definitely; 
there  are  reasons  for  believing  that  the  exaggerated  heat  production 
is  the  primary  fact,  the  result  of  hyperactivity  of  the  thyroid  body. 

To  summarize  therefore:  no  increase  in  heat  production  can  result 
in  fever  if  the  mechanism  of  heat  dissipation  is  normal;  the  essential 
abnormality  in  fever  lies  in  defective  dissipation  of  heat,  through  dis- 
turbance of  conduction,  radiation  and  perspiration;  heat  production 
may  be  primarily  increased  to  a  moderate  extent  in  fevers;  in  high 
fever,  the  production  of  heat  is  secondarily  augmented;  clinical  fevers 
may  be  associated  with  normal  production  of  heat,  with  subnormal 
production  or  with  excessive  production  of  heat;  a  moderate  reduction 
in  the  faculty  of  heat  dissipation  is  sufficient  to  produce  fever  in  a  body 
presenting  only  the  basal  minimal  production  of  heat. 


534  BODY  HEAT  AND  BODY  TEMPERATURE 


THE   PROCESSES  OF   OXIDATION,    SUBOXIDATION, 
SUPEROXIDATION 

The  processes  of  oxidation  in  the  body,  viewed  as  a  total,  possess 
an  interest  that  is  historical  rather  than  experimental.  The  several 
qualitative  reactions  of  the  oxidation  of  the  end  products  of  the  different 
metabolisms  have  been  indicated  in  their  appropriate  sections.  It  is 
a  law  that  the  components  of  the  body  are  not  subject  to  oxidation 
in  the  states  in  which  they  circulate.  Protein,  sugar,  glycogen  and 
fat — all  must  be  split  before  they  are  subject  to  oxidation.  Protein 
must  be  hydrolyzed  to  amino-acids,  these  must  be  deaminized,  a 
fraction  converted  into  sugar,  a  fraction  subjected  to  direct  oxidation. 
Fat  must  be  split  into  fatty  acid  and  glycerol,  the  glycerol  is  converted 
into  sugar,  the  fatty  acids  are  subject  to  oxidation  in  stages.  Glucose 
must  be  split  into  lactic  acid,  which  in  the  opinion  of  the  writer  is 
then  converted  into  carbon  dioxid  and  ethyl  alcohol,  which  is  oxidized 
in  stages.  Everywhere  is  the  sequence:  cleavage  — »  oxidation.  The 
oxidation  of  sugar  and  probably  of  fat  occurs  largely  in  the  muscles; 
the  oxidation  of  the  end  products  of  the  catabolism  of  protein  occurs 
largely  in  the  liver,  where  also  some  oxidation  of  fat  undoubtedly 
occurs. 

The  actual  modus  operandi  of  the  processes  of  oxidation  within 
the  body  is  not  well  understood.  Oxidation  ferments  are  necessarily 
concerned,  but  experimental  investigation  with  these  super-labile 
enzymes  is  very  unsatisfactory.  It  is  clear  that  concerned  in  oxida- 
tions in  tissues,  animal  and  plant,  are  ferments  of  three  types :  oxi- 
dases, peroxidases,  and  catalases.  The  present  conception  of  oxida- 
tion in  the  world  of  organic  and  inorganic  matter  regards  oxidation  as 
a  series  of  reactions  in  successive  oxid  stages.  While  these  successive 
oxid  stages  are  to  be  regarded  as  intermediary  peroxidations,  it  is 
certain  that  activated  oxygen  in  the  sense  of  ozone  is  not  essential. 
It  is  certain,  in  the  broadest  sense,  that  the  body  oxidations  are  not 
related  to  atmospheric  ozone.  The  very  function  of  the  oxidation 
ferments  is  to  attach  atomic  oxygen  to  the  ubstances  to  be  burned. 

In  the  chain  of  processes  whereby  oxygen  is  brought  to  the  tissues 
are  many  opportunities  for  abnormal  inhibitions.  The  oxygen  must 
first  be  taken  from  the  air  and  gotten  to  the  pulmonary  lining 
membrane;  it  must  then  be  absorbed  through  the  pulmonary  lining 
membrane;  it  must  then  be  taken  up  by  hemoglobin;  it  must  then  be 
transported  to  the  tissues;  in  the  tissues  it  must  react  with  the  sub- 
stances to  be  burned;  the  products  of  the  oxidation  must  be  removed 
from  the  tissues;  the  carbon  dioxid  must  be  carried  to  the  lungs;  from 
the  lungs  finally  the  carbon  dioxid  must  be  transferred  to  the  expired 
air.  In  this  long  chain  of  processes  are  certainly  opportunities  for 
lags  and  breaks.  The  general  concept  of  suboxidation,  really  rather 
as  a  term  than  as  a  quantitative  notion,  has  long  been  prominent  in 


OXIDATION,  SUBOXIDATION,  SUPEROXIDATION  535 

medical  writings.  And  in  a  great  many  diseases  concerning  organs 
that  have  a  role  in  one  or  other  of  these  stages,  the  idea  became  general 
that  suboxidation  was  a  result  of  the  disease.  This  idea  is  incorrect. 
While  it  cannot  be  stated  that  a  total  suboxidation  never  occurs  in  the 
body,  it  is  certain  that  a  total  suboxidation  must  be  the  rarest  phe- 
nomenon and  not,  as  usually  inferred,  a  common  one.  The  absorption 
of  oxygen  does  not  provoke  metabolism,  nor  is  metabolism  modified 
by  variations  in  the  oxygen  content  of  the  blood  under  conditions 
of  respiration;  it  is  the  metabolism  that  determined  the  absorption  of 
oxygen. 

Suboxidation.  —  Qualitative  suboxidations,  of  course,  occur.  The 
diabetic  cannot  burn  glucose,  and  cannot  burn  /?-oxy-butyric  and 
aceto-acetic  acid.  The  cystinuric  cannot  burn  cystin.  The  alcap- 
tonuric  cannot  burn  homogentisic  acid.  But  qualitative  oxidation  is 
not  what  is  understood  in  the  idea  of  suboxidation  that  is  current  in 
the  medical  profession. 

Now  the  fundamental  fact  of  metabolism  is  that  the  oxidation 
processes  depend  upon  the  oxidizable  substances  and  not  upon  the 
oxygen.    We  may  sketch  the  general  reaction  as  follows: 

Oxidizable  substrate  +  oxygen  +  oxidation  ferment  =  oxidation 
products  +  free  ferment.  Despite  superficial  appearances  to  the 
contrary,  the  analysis  of  clinical  data  and  experimental  evidence  alike 
indicates  that  there  is  no  failure  on  the  part  of  the  oxygen;  failure  if 
such  occurs,  lies  with  the  substrate  or  the  ferments.  It  is  a  common 
idea  that  respiration  of  air  poor  in  oxygen  fails  to  sustain  the  normal 
plane  of  total  oxidation;  this  is  an  error.  There  is,  of  course,  a  degree 
of  rarefication  of  oxygen  that  leads  to  failure  in  the  reactions,  but 
such  is  never  to  be  observed  in  ordinary  life.  It  is  a  common  idea  that 
in  diseases  of  the  lungs  the  entrance  of  oxygen  into  the  blood  is  diffi- 
cult, or  indeed  only  partially  accomplished.  Cyanosis  does  occur,  and 
labored  respirations  are  often  necessary.  But  the  total  oxidation 
of  such  subjects,  whenever  it  has  been  tested,  has  been  found  to  be 
normal,  if  indeed  it  was  not  above  normal.  Whether  the  use  of  com- 
pressed oxygen  in  pneumonia  does  actually  accomplish  the  introduction 
of  extra  oxygen  is  a  mooted  question.  But  in  any  event,  it  is  known  that 
the  total  oxidation  in  pneumonia  is  supernormal.  This  does  not  deny  the 
efficacy  of  inhalations  of  oxygen  in  pneumonia;  it  merely  indicates  that 
this  supposed  favorable  action  of  compressed  oxygen  cannot  rest  on  the 
removal  of  a  condition  of  suboxidation,  since  none  such  existed.  The 
normal  individual  absorbs  no  more  oxygen  from  an  atmosphere  of  pure 
oxygen  than  from  natural  air.  It  has  been  believed  that  in  certain  chronic 
indurative  conditions  of  the  lungs  the  exchange  of  gases  is  retarded 
and  incomplete.  The  oxygen  may  have  difficulty  in  passing  the  aveolar 
mucous  membrane  and  entering  the  capillary  spaces;  but  it  is  accom- 
plished, because  the  total  oxidation  is  normal.  In  connection  with 
valvular  diseases  of  the  heart,  when  one  considers  the  difficulties  in 
the  maintenance  of  the  normal  blood  pressure  and  velocity  of  the 


536  BODY  HEAT  AND  BODY  TEMPERATURE 

flow  of  the  blood  stream,  it  is  obvious  that  defective  transportation 
of  oxygen  to  the  tissues  might  occur.  Probably  it  does  occur  as  a 
very  acute  situation,  since  under  conditions  of  sudden  failure  of  the 
circulation,  large  amounts  of  lactic  acid  appear  in  the  urine,  and  lactic 
acid  is  known  to  appear  with  deprivation  of  oxygen.  As  an  acute 
condition  suboxidation  probably  occurs  in  sudden  dilatation  of  the 
heart,  in  sudden  pneumothorax,  and  in  surgical  and  traumatic  shock; 
but  it  is  clear  that  the  condition  cannot  be  more  than  transient.  In 
the  usual  case  of  valvular  disease,  labored  though  the  efforts  of  the 
circulation  may  be,  they  accomplish  the  transportation  of  oxygen 
in  a  competent  manner,  for  the  total  oxidation  of  the  body  is  normal. 
In  profound  anemia  the  hemoglobin  content  of  the  unit  of  blood  (either 
by  reduction  in  individual  cells  or  by  reduction  in  number  of  cells) 
may  fall  to  a  fifth  of  the  normal.  Yet  this  amount  of  hemoglobin  is 
able  to  carry  to  the  tissues  of  the  resting  or  inactive  patient  all  the 
oxygen  needed  by  the  body.  Than  this,  there  is  no  better  illustration 
of  the  faculty  of  compensation  and  adaptation,  the  capacity  for  over- 
load. What  under  all  the  named  conditions  may  be  lost  and  in  fact 
often  is  lost,  is  the  capacity  for  overload.  Under  all  circumstances 
with  which  we  are  acquainted,  the  tissue  capacity  for  oxygen  is  normal. 
Thus  in  diseases  of  all  kinds — acute  and  chronic  pulmonary  disease, 
valvular  and  muscular  heart  disease,  the  essential  anemia?,  in  tuber- 
culosis, in  cachexia?,  in  the  wasting  diseases,  in  carcinoma,  in  muscular 
dystrophies — whenever  and  however  examined,  the  total  combustions 
of  the  body  are  either  normal  or  above  the  normal.  The  unfortunate 
diabetic,  who  cannot  burn  sugar  and  who  obtains  from  fat  and  protein 
only  part  of  their  energy,  still  has  a  total  combustion  of  at  least  the 
normal  and  in  many  instances  certainly  above  the  normal,  though 
to  secure  this  heat  he  must  burn  incompletely  a  greatly  increased 
quantity  of  protein  and  fat.  The  machine  that  is  out  of  adjustment 
required  more  power  to  run  it;  so  does  the  human  function  when  out 
of  adjustment — if  there  be  any  change  it  is  in  the  direction  of  loss. 
Under  these  circumstances,  the  idea  of  total  suboxidation  has  no 
standing  in  modern  pathology.  A  current  idea  of  suboxidation  as 
related  to  distoxication  of  hypothetical  metabolic  substances,  repre- 
sents simply  a  verbal  explanation  of  a  hypothetical  situation,  and  has 
no  experimental  foundation.  What  is  needed  in  the  study  of  distoxica- 
tion is  experimentation,  not  speculation. 

There  are  three  chronic  conditions  in  which  the  gross  data  have 
suggested  a  low  plane  of  total  oxidation — possibly  not  abnormal  but 
certainly  low.  These  are  obesity,  myxedema,  and  castration.  To 
assume  for  any  one  of  these  a  total  suboxidation  is  to  assume  a  reduc- 
tion in  the  basal  production  of  heat,  for  which  we  have  otherwise  no 
illustration.  In  the  discussion  of  the  total  basal  production  of  heat, 
it  was  pointed  out  that  this  is  in  part  an  individual  variable;  and  that 
in  some  cases,  very  low  values  had  been  found.  Such  a  subject  would 
naturally  incline  to  obesity.    This  is  one  thing.    But  it  is  a  very  different 


OXIDATION,  SUBOXIDATION,  SUPER0XIDAT10N  537 

thing  to  believe  that  in  a  particular  individual,  following  the  establish- 
ment of  obesity  or  myxedema  or  following  castration,  the  body  changes 
its  plane  of  basal  heat  production  to  a  lower  level.  A  great  deal  of 
misconception  has  been  due  to  the  low  heat  production  per  kilo  in  the 
obese.  But  it  is  in  just  these  instances  that  the  defect  of  this  method 
of  calculation  is  pronounced.  A  man  weighs  at  full  manhood  70  kilos. 
Later  in  life  he  grows  very  fat,  the  weight  increases  even  to  140  kilos. 
The  heat  production  is  related  to  the  metabolic  tissues,  under  condi- 
tions of  control,  not  to  the  mass  of  the  fat  depots.  This  same  man  with 
the  normal  heat  production  per  unit  of  surface  area  would  when  fat 
present  little  more  than  half  as  much  heat  in  terms  of  Calorie  per  kilo  as 
in  his  natural  state.  The  real  question  is:  What  is  the  basal  heat  pro- 
duction of  the  body?  Is  it  below  the  amount  seen  in  normal  individuals 
with  low  basal  heat  production?  There  is  no  evidence  that  this  is 
ever  the  case.  There  is  no  evidence  that  an  animal  has  ever  changed 
his  basal  heat  production  through  myxedema  or  after  castration. 
The  three  conditions  named  all  tend  to  minimize  the  other  fractions 
of  heat  production.  The  subjects  are  inactive  in  every  sense.  Castra- 
tion and  thyroid  extirpation  convert  a  nervous  into  a  phlegmatic  consti- 
tution. The  diets  are  usually  low,  under  the  conditions  of  experimenta- 
tion or  observation,  and  the  heat  of  the  specific  dynamic  action  of  protein 
is  low.  Cretins  and  the  subjects  of  myxedema  have  a  low  nitrogenous 
metabolism.  With  a  heavy  layer  of  fat  and  thickened  skin  and  subcu- 
taneous infiltration  in  myxedema,  physical  regulation  of  temperature 
is  extremely  effective,  and  heat  production  is  spared  in  this  way.  In 
other  words,  these  very  subjects  present  the  best  opportunities  for 
the  measurement  of  the  basal  heat  production.  So  far  as  we  know, 
the  basal  heat  production  of  each  body  is  a  constant  to  that  body, 
to  the  mass  of  cells  of  that  body  and  to  the  surface  area;  and  this  law 
is  inexorable.  The  body  has  marked  faculty  for  increase  in  heat  pro- 
duction; but  there  is  no  adaptation  for  reduction  in  the  basal  heat 
production. 

There  are  three  conditions  in  which  most  extreme  exaggeration  in 
heat  production  and  total  metabolism  may  occur,  cellular  in  origin 
and  not  due  to  muscular  movements.  These  are  exophthalmic  goitre, 
malignant  disease,  and  sepsis.  In  the  severe  instances  of  these  diseases 
(in  the  so-called  fulminating  cases  of  exophthalmic  goitre,  in  the  stage 
of  rapid  growth  of  malignant  tumors  and  proportional  wasting  of  the 
body,  in  profound  bacterial  intoxications)  it  is  impossible  to  secure 
either  a  nitrogenous  or  a  caloric  equilibrium,  no  matter  what  the  input 
in  the  diet.  It  is  true  that  the  powers  of  digestion  and  assimilation 
are  often  low.  But  the  actual  transformations  in  the  metabolism, 
the  output  of  nitrogen  and  of  carbon  dioxid,  are  very  high;  and  food 
only  seems  to  feed  the  flame.  Evidently  we  deal  in  these  cases  with 
great  exaggeration  of  enzymic  accelerations,  due  to  direct  action  of 
poisons  developed  in  these  diseases.  The  thyroid  gland  is  known  to 
stimulate  the  several  metabolisms.    In  direct  experiment  it  is  demon- 


538  BODY  HEAT  AND  BODY  TEMPERATURE 

strable  that  thyroid  substance  increases  the  nitrogenous  catabolism 
and  the  combustions  in  the  body.  In  exophthalmic  goitre  we  have 
evidently  an  abnormal  and  excessive  production  of  the  substances 
that  so  act  upon  these  metabolic  processes.  Future  investigations 
with  the  respiration  apparatus  will  doubtless  reveal  to  us  many  new 
manifestations  of  exaggerations  of  one  or  the  other  metabolism,  and 
indicate  new  points  of  relationship.  When  one  recalls  the  direct  con- 
nection of  metabolism  with  diet,  there  can  be  no  question  that  such 
knowledge  is  certain  to  have  practical  bearings. 

THE   RELATIONS    OF   WORK .  TO   METABOLISM 

The  unit  of  work  used  in  physiology  is  the  kilogrammeter,  the  work 
required  to  lift  one  kilo  one  meter  against  the  force  of  gravity.  The 
kilogrammeter  is  equal  to  about  97.63  megaergs  and  to  about  7.2 
foot-pounds.  It  corresponds  to  about  0.00236  Calorie  of  heat.  The 
maximum  work  that  a  trained  man  can  do  does  not  probably  exceed 
1800  kilogrammeters  per  minute,  and  this  cannot  be  long  sustained. 
For  the  whole  day,  it  is  doubtful  if  more  than  one-third  that  can  be 
accomplished.  Calculated  for  the  whole  day,  that  would  correspond 
to  the  production  of  over  20,000  Calories  of  heat,  even  with  the 
mechanical  efficiency  of  the  work  being  set  at  30  per  cent.  We  have 
no  data  tending  to  show  that  more  than  half  this  work  can  be  accom- 
plished in  a  day  by  a  trained  man.  The  work  of  walking  on  the  level 
at  moderate  pace  may  be  roughly  stated  to  equal  one  Calorie  per  kilo 
body  weight  per  mile. 

The  source  of  the  energy  converted  into  work  lies  in  the  combus- 
tions of  the  body.  None  of  the  heat  of  the  basal  production  of  heat 
is  convertible  into  work;  if  work  be  done,  more  heat  is  set  free.  The 
heat  of  the  specific  dynamic  action  of  the  foodstuffs  is,  however,  con- 
vertible into  work.  In  other  words,  an  amount  of  work  whose  doing 
is  associated  with  the  production  of  some  300  Calories  of  heat  can 
be  done  by  the  individual  whose  diet  possesses  that  value  in  specific 
dynamic  action,  without  there  being  any  additional  heat  production; 
working  up  to  that  amount  or  resting,  the  heat  production  of  the 
body  will  be  the  same. 

The  heat  of  chemical  regulation  is  convertible  into  work.  If  an 
individual  inured  to  external  cold  be  exposed  to  a  certain  outside 
temperature,  his  heat  production  in  the  resting  state  will  rise,  let 
us  say  for  a  certain  experiment,  600  Calories.  Now  if  under  identical 
circumstances,  an  amount  of  work  be  done  that  is  associated  with  the 
production  of  600  Calories  of  heat,  the  total  heat  production  will  be 
found  not  to  have  risen  above  the  figure  for  the  first  experiment.  The 
needed  heat  is  produced  by  work  and  spared  from  chemical  regulation. 

Work,  in  the  usual  sense  of  the  term,  involves  so  large  an  amount 
of  energy  transformation  as  to  exceed  the  heat  of  the  specific  dynamic 
action  of  the  foodstuffs  and  the  heat  of  chemical  regulation.    There- 


THE  RELATIONS  OF  WORK  TO  METABOLISM  539 

fore,  work  usually  implies  an  extra  production  of  heat.  The  mechanical 
efficiency  of  muscular  contractions  varies  usually  from  20  to  25  per 
cent.,  i.  e.,  of  the  total  heat  value  of  the  fuel  burned  to  support  work, 
75  to  80  per  cent,  appears  as  heat,  and  20  to  25  per  cent,  is  transformed 
into  work.  This  is  about  the  efficiency  of  a  good  steam  engine.  Higher 
values  are  not  recorded  in  trained  individuals,  but  are  noted  for  certain 
forms  of  work.  Thus  in  walking,  in  a  trained  individual  about  35  per 
cent,  of  the  heat  value  is  converted  into  work. 

Light  work  entails  the  combustion  of  food  worth  about  800  Calories; 
medium  work  represents  the  combustion  of  food  worth  about  1200 
to  1500  Calories;  heavy  work  represents  about  2400  Calories;  and 
excessive  or  maximum  work  as  high  as  8000  Calories  per  day.  This 
may  be  shown  in  a  table  taken  from  Benedict  and  Carpenter. 

Calories  per  hour 

Metabolism  during  rest 92 

Metabolism  during  work 619 

Metabolism  due  to  work 527 

Heat  equivalent  of  work  measured 112 

Mechanical  efficiency  in  percentage 21.3% 

This  experiment  was  done  on  a  professional  bicycle  rider,  and  these 
riders  often  ride  at  such  a  pace  for  twenty-two  or  twenty-three  hours 
per  day.  If  this  subject  had  ridden  twenty-three  hours  per  day,  the 
values  would  have  been: 

Calories  per  day. 

Metabolism  of  rest 2,116 

Metabolism  of  work 12,121 

Heat  equivalent  of  work  measured 2,576 

Total  combustion  equaling 16,813 

To  support  such  an  output,  the  body  must  have  burned  an  amount  of 
food  that  in  isodynamic  figures  would  read  something  like  this: 

Calories. 

Protein,  200  grams 840 

Carbohydrate,  600  grams 2,400 

Fat,  1520  grams ,  .      .      .      14,280 

No  such  amount  of  food  could  be  ingested;  it  is  burned  from  the  tissues 
of  the  individual.  Mixed  diets  have  been  measured  as  actually  con- 
sumed by  men  in  severe  work  as  follows,  in  rounded  figures:  protein, 
500  grams;  carbohydrate,  500  grams;  fat,  850  grams,  in  total  repre- 
senting over  11,000  Calories.  These  are  very  extreme  figures.  The 
average  normal  individual  cannot  accomplish  half  as  much  work  as 
above  stated,  or  eat  half  as  much  food. 

The  mechanical  efficiency  is  little  increased  by  training,  if  at  all. 
Training  enlarges  the  powers  of  the  circulation  and  respiration,  of 
digestion  and  assimilation.  It  increases  the  number  of  a  particular 
movement  that  can  be  done  in  the  unit  of  time  and  extends  the  period 


540  BODY  HEAT  AND  BODY  TEMPERATURE 

of  time  through  which  work  can  be  sustained.  But  it  does  not  mate- 
rially increase  the  mechanical  efficiency  of  a  particular  movement. 

The  combustions  for  the  support  of  work  first  attack  the  carbo- 
hydrates of  the  body;  and  if  these  be  present  or  supplied  up  to  the 
need,  work  will  be  supported  by  combustion  of  carbohydrate  alone. 
The  actual  efficiency  of  work  done  on  combustion  of  glucose  is  little 
if  any  greater  than  in  the  case  of  the  combustion  of  fat.  But  the  body 
burns  sugar  in  preference  to  fat  if  choice  be  presented.  The  respiratory 
quotient  is  high  in  the  beginning  of  a  forced  march;  late  in  the  march 
it  falls,  indicating  the  combustion  of  fat.  If  sugar  be  supplied  (it  is 
now  included  in  the  forced-march  ration  of  many  armies),  the  quotient 
remains  high.  The  sugar  reaches  the  tissues  of  combustion  in  thirty 
to  fifty  minutes  after  ingestion ;  and  the  sugar  ration  has  advantageously 
replaced  the  grog  ration  of  our  forefathers.  With  normal  work,  espe- 
cially if  uniform  and  done  by  trained  muscles,  the  respiratory  quotient 
is  the  same  during  work  as  at  rest;  but  with  excessive  work,  especially 
in  spurts  to  the  point  of  the  fatigue  or  with  untrained  muscles,  the 
respiratory  quotient  will  often  rise  for  a  short  time,  later  to  fall. 

In  the  absence  of  sugar,  the  body  will  burn  fat  (of  the  diet  or  fat 
from  the  body  depots)  for  the  support  of  work,  though  the  efficiency 
is  a  little  lower  than  in  the  case  of  sugar.  For  extreme  exertions,  how- 
ever, fat  is  the  better  food,  since  it  is  possible  to  ingest  in  a  day  more 
calories  in  the  state  of  fat  than  in  the  form  of  sugar.  The  diet  should, 
however,  always  contain  enough  carbohydrate  to  avoid  acidosis  and 
to  save  the  catabolism  of  excessive  protein. 

In  the  presence  of  carbohydrate,  the  catabolism  of  protein  is  not 
modified  or  exaggerated  by  muscular  work.  Very  excessive  work,  and 
especially  work  with  untrained  muscles,  may  lead  to  increase  in  total 
nitrogenous  catabolism  and  an  increase  in  creatinin,  but  this  is  an 
abnormal  reaction.  Normally,  work  does  not  affect  the  protein  catab- 
olism, it  does  not  affect  the  nucleic  or  creatin-creatinin  metabolism. 
In  a  word,  physical  work  under  normal  conditions  does  not  noticeably 
affect  the  up-keep  and  wear-and-tear  of  the  cells.  In  the  absence 
of  carbohydrate  and  fat,  heavy  work  can  be  supported  on  the  com- 
bustion of  exogenous  protein  alone,  but  it  is  an  extravagant  process. 
And  under  such  circumstances,  the  endogenous  protein  catabolism  is 
also  exaggerated. 

At  high  altitudes,  the  mechanical  efficiency  of  work  is  reduced  and 
the  capacity  for  work  is  also  lowered.  On  the  other  hand,  the  resting 
metabolism  is  greater  than  at  sea  level.  These  results  are  not  effects 
that  are  developed  pari  passu  with  each  meter  of  ascent,  but  they  appear 
when  the  oxygen  content  of  the  air  approaches  a  certain  low  figure. 
The  altitude  at  which  metabolism  in  the  resting  individual  is  increased 
is  about  12,000  feet,  though  it  is  lower  for  some  than  for  others.  Some 
individuals  tolerate  an  atmosphere  so  rare  as  to  contain  only  10  per 
cent,  of  oxygen,  better  than  others  are  able  to  endure  an  atmosphere 
with  over  12  per  cent,  of  oxygen.    The  pressure  of  oxygen  within  the 


THE  RELATIONS  OF  WORK  TO  METABOLISM  541 

alveoli  of  the  lungs  at  sea  level  varies  from  100  to  110  mm.  Hg.;  at  an 
altitude  of  15,000  feet  it  is  reduced  one-half.  This  has  its  effect,  of  course, 
upon  the  combination  of  hemoglobin  with  oxygen.  At  sea  level  the 
hemoglobin  of  arterial  blood  is  about  90  per  cent,  saturated  when 
absorption  is  complete;  in  actual  life  it  is  not  over  80  per  cent.  At 
15,000  feet  altitude,  the  degree  of  saturation  would  be  reduced  to 
65  per  cent.  The  fact  that  the  actual  total  combustion  at  15,000  feet 
is  increased  by  some  15  per  cent,  indicates,  however,  that  oxygen 
reaches  the  tissues  in  abundance.  From  the  total  data  one  cannot 
resist  the  conviction  that  the  causes  of  the  decreased  mechanical  efficiency 
and  lowered  capacity  for  work  noted  at  high  altitudes  are  physical 
rather  than  chemical. 

There  is  no  thermic  equivalent  for  mental  work.  Resting  in  the 
calorimeter  without  mental  work,  a  subject  displays  the  same  output 
of  heat  as  when  engaged  in  the  solution  of  a  mathematical  problem. 
Our  measurements  have  of  course  a  certain  range  of  error,  plus  and 
minus;  and  it  is  possible  that  a  small  production  of  heat  would  not  be 
noticed.  The  fact  is  striking  enough,  in  view  of  the  variations  in 
circulation  that  have  been  assumed  to  attend  mental  effort.  The  fact 
has,  however,  no  bearing  on  the  application  of  the  law  of  the  conserva- 
tion of  energy  to  biological  processes;  any  inference  to  that  effect  rests 
upon  a  misconception  of  thermodynamics. 


INDEX 


A 


Acapnia,  glucosuria,  286 
Acetic  acid,  combustion  of,  353 
Aceto-acetic  acid,  combustion  of,  353 
conversion  into  acetone,  68 
derivation   from   histidin,    360, 
416 
from  phenylalanin,  360 
in  combustion  of  aromatic 
amino-acids,     410,     411, 
412 
oxidation  of,  in  diabetes,  328 
source  of  acetone,  353 
Acetone  bodies,  derivation  from  protein, 
359 
elimination  of,  in  diabetes,  329 
origin  from  fat,  361 
complex,  358,  465 

after  narcosis,  364 
derivation  from  alanin,  359 
from  histidin,  359 
from  leucin,  359 
from  phenylalanin,  359 
from  ty rosin,  359 
formation  of,  in  diabetes,  328 
origin  from  aceto-acetic  acid,  353 
polymerization      into       di-acetone 
alcohol,  57 
Acrolein,  formation  from  glycerol,  1Q1 
Acromegaly,  relation  to  diabetes,  297 
Acidosis,  358,  369,  465 
distoxication,  330 
in  diabetes,  362 
in  eclampsia,  363 
in  infections,  362 
in  phloridzin  intoxication,  362 
in  phosphorus  poisoning,  364 
in  starvation,  362 
ketonuric,  330 
mechanism  of,  406 
neutralization  by  bases,  320 
relations  in  tissues  in  diabetes,  332 
to  combustion  of  glucose,  364 
to  glucose  toleration  in  diabetes, 
333 
Acids,  volatile,  in  urine  in  diabetes,  332 
Adenin,  conversion  into  hypoxanthin,  439 

structure  of,  432 
Adenosin,  430 

Adrenal  bodies,  relation  of  ablation  to 
hypoglucemia,  285 


Adrenal  bodies,   relation  of,  to  glucose 

combustion,  265 
Air  currents,  relation  to  heat  dissipation, 
524 
expired,  toxic  proportions  of,  463 
Alanin,  30 

conversion  into  lactic  acid,  395 
in  oxyproteic  acid,  389 
source  of  acetone,  359 
of  glucose,  391,  392 
of  glycerol,  274 
of  lactic  acid,  268 
Alcaptonuria,  410,  411,  412,  413,  467 
Alcohol,  addition  to  amino-acids,  31 
ethyl,  acetous  fermentation,  64 
Aldehyd,  conversion  into  paraldehyd,  57 
Aldohexoses,  description  of,  20 
Aldoses,  definition  of,  18 
Alkalinity  of  blood,  relation  to  gout,  458 

of  intestinal  contents,  154 
Allantoin,   cleavage  into  urea  and  gly- 
oxylic  acid,  449 
in  urine,  417 

relation  to  uric  acid,  448 
All-oxy-proteic  acid,  in  urine,  417 
Altitude,    influence   on   mechanical   effi- 
ciency of  work,  541 
on  metabolism,  541 
on  work,  541 
Amino-acid,  addition  of  alcohol,  31 
of  formaldehyd,  31 
content  in  proteins,  38 
in  proteins,  31 
Amino-acids,    bacterial    action    on,    in 
alimentary  tract,  218 
biuret  reaction  of,  31 
catabolism  of,  407 
deaminization  of,  67,  395 

within  intestinal  tract,  193 
in  feces,  214 
in  peptic  digestion,  139 
in  urine,  396,  417 

in  diabetes,  314 
linkage  of,  in  molecule  of  protein,  39 
list  of  sugar  builders,  393 
new  formation  of,  379 
relation  to  specific  action  of  protein, 

475 
resorption  of,  192 
source  of  creatin,  424 

of  glucose,  385,  390 
synthesis  of,  378 


544 


INDEX 


Amino-acids,  synthesis  of,  to  protein  in 

intestinal  wall,  194 
Amino-butyric  acid,  derivation  from  a- 

keton-butyric  acid,  379 
Amino-purin,  deaminization  of,  440 
Amino-purins  in  beverages,  447 
Amino-pyrimidin,  deaminization  of,  440 
Amino-sugar,  391 
Ammonia,  derivation  of,  385 

formation  by  bacteria  in  intestine, 
405 
by    deaminization    of    amino- 
acids,  405 
by  intestinal  deaminization,  405 
in  hydrolysis  of  protein,  405 
in  protein,  37 
in  urine,  405 

in  acidosis,  321 
primary,  407 
relation  to  acidosis,  405,  406 
to  alkalosis,  405 
Ammonia-urea,  equilibrium,  405 
Ammonium    aldehyd,     conversion    into 
beta-oxy-butyric  acid,  365 
carbamate,  399 
carbonate,  source  of  urea,  399 
Amphoterism,  in  proteins,  27 
Amylase,  in  intestinal  secretion,  168 
in  pancreatic  secretion,  115,  157 
in  succus  entericus,  115 
salivary,  119 
Anabolism  of  fat,  346 

of  nucleic  acid,  434,  441 
of  protein,  373 

adaptation  in,  381 
Anemia,  oxidation  in,  536 
Anthracin,  relation  to  dianthracin,  57 
Antiseptic  action  of  bile,  179 
Antiketonic  substances,  in  diabetes,  333 
d-Arabinose,  231 
1-Arabinose,  231 

Areolar  tissues,  formation  of  fat,  259 
Arginase  in  liver,  396,  398 
Arginin,  37,  41 

cleavage  of,  396 

hydrolysis  of,  62 

Aromatic  amino-acids,  409 

bodies  in  urine,  relation  to  bacterial 
action,  409 
to  metabolism,  409 
Arsenic  trioxid,  conversion  into  cacodylic 
oxid,  66 
reduction  of,  66 
Asparagin,  35 
Aspartic  acid,  35 

reduction  to  ammonium  succi- 
nate, 67 
source  of  beta-oxy-butyric  acid, 
360 
of  glucose,  393 
synthesis  of,  378 
Assimilation  of  carbohydrate,   limit  of, 

249 
Autointoxication,  461 


Autointoxication    by   formation   of    ab- 
normal substances,  466 

by  intermediary  metabolic  products, 
465 

by  overload,  467 

by    retention    of    end   products    of 
metabolism,  463 

gastro-intestinal,  462 

relation  to  alimentary  secretions,  467 

through  failure  of  distoxication,  466 

toxicity  of  cutaneous  secretions,  464 
Autolysis  in  involution  of  uterus,  389 

in  pneumonia,  389 

in  tuberculosis,  389 

of  cellular  protein,  385 
Aut-oxy-proteic  acid  in  urine,  417 


B 


Bacteria,  action  on  foodstuffs  in  alimen- 
tary tract,  217 
on  nucleosid,  433 
assimilation  of  protein,  375 
digestion  without,  49 
Bacterial  conditions  in  alimentary  tract, 
abnormal  result  on  digestion,  204, 
206 
intoxication,  gastro-intestinal,  461 
Balance,  nitrogen,  418 
Basal  heat  production,  509 
Benzene  bodies,  relations  of  reaction  to 
configuration,  106 
ring,  mode  of  rupture  in  body,  409 
Benzoic   acid,    derivation   from   phenyl- 
alanin  in  intestine,  219, 
226 
from   tyrosin   in   intestine, 
219 
Benzol  combustion  in  diabetes,  305 
Bernard  puncture,  249,  283 
Beta-oxy-butyric   acid   and   aceto-acetic 
acid,     equilibrium     between, 
361 
combustion  of,  353 

in  diabetes,  307 
derivation   from   aspartic   acid, 
360 
from  leucin,  359 
formation  from  ammonium  alde- 
hyd, 361 
Bile,  170 

antiseptic  action  of,  179 

bilirubin,  175 

cholesterol  in,  178 

cholic  acid,  172 

functions  of,  179 

glycocoll  in,  173 

in  feces,  216 

influence  on  peristalsis,  179 

in  stomach,  146 

intestinal  digestion  in  the  absence 

of,  181 
lipoids  of,  177 


INDEX 


545 


Bile,  nitrogenous  bodies  in,  178 
pathological  variations,  180 
phosphorus  compounds  of,  177 
proteins  in,  171 

quantitative  components  of,  170 
relation  to  cleavage  of  fat  in  intes- 
tine, 180 
to    digestion    of    carbohydrate, 
179 
of  protein,  179 
to  resorption  of  fatty  acids,  180, 

181 
to  solution  of  fat  in  intestine, 
180 
secretion  of,  178 
sulphur  compounds  in,  171 
taurin,  172 

zymo-excitor  action  on  lipase,  159, 
180 
Biliary  acids  in  feces,  174 
Bilirubin  in  bile,  175 
constitution  of,  175 
derivation  from  erythrocytes,  175 
Biliverdin,  formation  from  bilirubin,  176 
Birds,  purin  output  in,  444 
Biuret  reaction  in  proteins,  31 
Blood  content  of  urea,  400 
in  fasting,  488 

pressure,  factor  in  intestinal  resorp- 
tion, 202 
protein,  concentration  of,  384 
state  of  fat  in,  344 
Body  heat,  conduction  and  radiation,  529 
production  of,  509 
surface,  determination  of,  518 
temperature,  regulation  of,  509,  517 
chemical,  518 
physical,  519 
weight  in  fasting,  488 
Bread,  purin  content  of,  446 
Butter  in  diet,  relation  to  ketonuria  in 

diabetes,  331 
Butyric  acid,  combustion  of,  352 
chart  of,  367 
derivation  from  triolein,  354 
formation  from  lactic  acid,  343 
oxidation  of,  in  diabetes,  328 
relation    of    combustion    of,    to 
glucose,  367 


Cadaverin,  derivation  from  lysin,  415 
Caffein,  446 

glucosuria,  284 
Caloric  content  of  body,  468 

equivalents  of  carbohydrate,  513 
in  diabetes,  300 
of  fat,  513 
of  protein,  513 
values  of  diets,  474,  502 
Calorimeter,  bed,  metabolism  in,  514 
Cane  sugar  in  metabolism,  241 


Caproic  acid,  combustion  of,  351 
origin  in  oleic  acid,  354 
Carbamino  acids,  399 
Carbohydrate,  caloric  equivalents,  513 
digestion    within    resorption    mem- 
brane, 190 
fasting,  490 
fuel  for  work,  540 
influence  on  protein  catabolism  in 

fever,  480 
limit  of  assimilation  of,  249 
metabolism,  230 
in  diabetes,  291 
in  fasting,  484,  487 
ration  in  diet,  500 
reciprocal  relation  to  fat  in  diet,  472, 

476 
resorption  of,  189 
respiratory  quotient,  513,  516 
saving  power  for  protein,  478 
Carbohydrates,    bacterial   action   on,  in 
intestine,  218 
caloric  value  of,  23 
description  of,  17 
Carbon  asymmetric,  19 

dioxid,  addition  to  amino-acids,  31 
elimination  in  diabetes,  340 
in  metabolism,  514,  515 
monoxid,   relation  to  formation  of 
formaldehyd,  65 
Carcinoma  of  stomach,  ferment  in,  170 
Cardiac  disease,  oxidation  in,  536 
Cartilage,    relation    of    composition    to 

urate  deposition,  458 
Casein,  anabolism  of,  377 
Castration,  oxidation  in,  536 
Catabolism  of  dead  cells,  383 
of  exogenous  protein,  384 
of  fat,  320 
of  protein,  383 
chart  of,  420 
in  fasting,  385 
of  protoplasm,  wear  and  tear,  383 
of  special  sugars,  237 
of  superfluous  amino-acids,  383 
Catalase,  534 

Catalysis,  application  of  laws  of,  to  fer- 
mentation, 70,  78 
in  heterogeneous  system,  87 
Catalyzer,  inactivation  of,  76 

relation  to  order  of  reaction,  75 
to  reaction,  74 
to  station  of  equilibrium,  75 
Cells,  autolysis  of,  385 

content  of  glycogen  and  glucose,  244 
regeneration  of,  374 
wear-and-tear  of,  374 
Cellulose,  hydrolysis  of,  60 

in  diet,  493 
Cerebron,  galactose  content,  234 
Cerebronic  acid,  234 
Chemical  nature  of  ferments,  94 
regulation,  518 

heat  production,  510 


35 


546 


INDEX 


Childhood,  metabolism  in,  505 
Chloroform,  necrosis  of  liver,  364 
Chlorophyl,  sugar  formation  by,  18 
Cholesterol,  349 

catabolism  of,  350 
in  bile,  178 
in  feces,  350 
Cholic  acid,  derivation  from  erythrocytes, 
173 
in  bile,  172 
Cholin,  348,  465 
Chondroitin,  236 

Chymosin,  individuality  as  ferment,  144 
in  gastric  secretion,  144 

variations  in  disease,  144 
in  intestinal  secretion,  169 
pancreatic  secretion,  160 
Circulation,  heat  production  of,  510 

of  skin,  relation  to  heat  dissipation, 
520 
Clothing,  relation  to  heat  dissipation,  525 
Coagulation  of  proteins,  28 
Cocoa,  purin  content  of,  446 
Coffee,  purin  content  of,  446 
Collagen,  anabolism  of,  376 
Colloidal  nature  of  proteins,  24 
Combined  sugar  in  tissues,  230 
Combustion  of  fat,  351 
of  glucose,  261 

in  muscles,  255 
Combustions  in  support  of  work,  540 
Conduction  and  radiation  of  body  heat, 
529 
in  fever,  531 
p-Cresol,    derivation    from    tyrosin    in 
intestine,  219 
oxidation  of,  410 
Creatin,  abnormal  appearance  in  urine, 
427 
administration  of,  425 
catabolism,  relation  to  metabolism  of 

glucose,  428 
-creatinin  metabolism,  469 
derivation  of,  424 
elimination  in  diabetes,  428 
in  inanition,  428 
in  muscular  degeneration,  428 
metabolism  of,  423 
relation  to  amino-acids,  424 
source  of  creatinin,  425 
Creatinin,  coefficient  of  muscular  metab- 
olism, 423 
conversion  into  urea,  400,  426 
derivation  from  creatin,  425 
elimination  of,  423 
endogenous,  424 
exogenous,  424 
metabolism  of,  423 
chart  of,  454 
specificity  of,  426 
in  work,  540 
output  in  urine,  425 
pathological    variations   in    elimina- 
tion of,  427 


Crystallization  of  protein,  27 
Cystein,  414 

derivation  from  erythrocytes,  173 

in  bile,  173 

source  of  glycerol,  274 
of  lactic  acid,  268 
Cysteinic  acid  in  bile,  173 
Cystin,  33,  41 

anabolism  of,  421 

catabolism  of,  414 

cleavage  in  intestine,  414 

in  urine,  396 

oxidation  of,  414 

relation  to  sulphur  metabolism,  421 

requirement  of,  378 
Cystinuria,  414,  465 

relation  to  diet,  415 
Cytidin,  occurrence  of,  437 
Cytosin,  conversion  into  uracil,  440 

in  urine,  459 

occurrence  of,  437 

structure  of,  431 


Deaminization  ferment,  440 
of  amino-acids,  385,  395 
of  amino-purins,  439 
of  amino-pyrimidin,  440 
within  intestinal  tract,  193 
Denaturation  of  proteins,  29 
Dextrinuria  in  diabetes,  308 
Diabetes,  acidosis  in,  362 

ammonia  as  index  of  acidosis  in,  331 
caloric  equivalents  in,  300 
carbon  dioxid  elimination  in,  340 
combustion  of  glucose,  297,  299,  300 

of  various  bodies  in,  305 
carbohydrate  metabolism  in,  291 
definition  of,  291 
derivation  of  glucose  from  protein, 

315 
elimination  of  acetone  bodies,  329 

of  creatin  in,  428 
etiology,  291 
experimental,  291 
failure    of    formation    of    fat    from 

glucose  in,  358 
fat  combustion  in,  327 
formation  of  fat  from  glycogen,  311 

of  sugar  from  fat,  326 
fructosuria,  235 
G  :  N  ratio  in,  316,  320,  321 
heat  production  in,  340 

value  of  protein  in,  326 
hepatic  glycogenesis  in,  309 

glycolysis  in,  310 
hypothesis  of  direct  combustion  of 

glycogen,  304 
influence  of  fever  on  combustion,  302 
lipemia  in,  335 
masked  in  obesity,  311 
mixed  melituria  in,  308 


INDEX 


547 


Diabetes,     muscular    glycogenesis     and 
glycolysis  in,  311 
O-absorption  in,  340 
overproduction  of  sugar  in,  306 
oxidation  in,  536 

of  butyric  acid  in,  328 
pancreatic,  298 
protein  metabolism  in,  313 
relation  of  acidosis  to  utilization  of 
glucose,  333 
of  glucose  to  lactic  acid,  292 
of  work  to  combustion  of  glu- 
cose, 302 
renal  retention  of  sugar,  307 
respiratory  quotient  in,  335,  337 
salt  of  the  urine,  332 
toleration  for  different  sugars,  303 
total  metabolism  in,  339 
utilization  of  calories  of  diet  in,  340 
volatile  acids  in  urine  in,  332 
Diabetic  coma,  amino-acids  in  urine  in, 

396 
Dialuric  acid,  conversion  into  uric  acid, 

445 
Diamins  in  urine,  417 
Diazo-amino-benzole,  conversion  into  p- 

amino-azobenzol,  58 
Di-brom  succinic  acid,   conversion  into 

bromo-maleic  acid,  59 
Diet,  bread,  mass  of,  184 
bulk  of,  493 

carbohydrate  ration  in,  500 
cellulose  in,  493 
definition  of  complete,  49 
desiderata,  493 
energy  content,  493 
fat  ration  in,  500 
fresh  food  in,  493 
mass,  relations  of,  181 
milk,  mass  of,  183 
normal,  493 
protein,  493 

mass  of,  184 
salts  in,  493 
vegetable,  mass  of,  185 
Diets,  caloric  values  in,  503 
Diffusion,  factor  in  intestinal  resorption, 
201 
of  protein,  26 
Digestion,   abnormalities  due  to   defect 
in  resorption,  204,  205 
to     qualitative     chemical 
variations,  204,  205 
disturbances  due  to  abnormal  motor 
functions,  204,  205 
to  abnormalities  in  secre- 
tion of  digestive  juices, 
204,  205 
to  bacterial  conditions,  204, 

206 
to  improper  mastication,  204 
to     quantitative     chemical 

variations,  204,  205 
to  toxic  ingesta  204 


Digestion,  functions  of,  113 

in  vitro,  114 

in  vivo,  118 

of  protein,  scope  of,  in  stomach,  139 

of  nucleo-protein,  432,  436 

postmortem,  385 

relations  of  heat  and  energy,  206 

resorption  of  products  of,  186 

salivary,  119 

in  vitro,  115 

without  bacteria,  49 

work  of,  474 
Dihydro-cholesterol,  350 
2-5-Dihydroxy-phenyl-pyruvic  acid,  411 
o-Dioxy-benzene,  derivation  from  tyrosin 

in  intestine,  219 
Dioxyphenyl-acetic  acid,  410 

lactic  acid,  410 
Disaccharids,  formation  from  monosac- 
charids  by  ferments,  87 

hydrolysis  of,  61 

in  metabolism,  241 
Disease,    gastric,    variations    of    hydro- 
chloric acid  in,  135 
Distearyl  lecithin,  349 
Distoxication,  466 
Duodenal  contents  in  stomach,  146 


Eck  fistula,  intoxication  in,  466 

urea  formation  with,  401 
Eclampsia,  acidosis  in,  363 
Elimination  of  end  products  of  protein 

catabolism,  417 
Emulsin  in  intestinal  secretion,  168 

in  pancreatic  secretion,  159 
Endogenous  protein,  elimination  of  end 
products  of,  418 
purin,  catabolism  in  gout,  455 
Energy  relations  in  digestion,  206 
Enterokinase  in  intestinal  secretion,  161 
Epiguanin,  440 
Epinephrin,  glucosuria,  285 
relation  to  tyrosin,  413 
Equation,  differential,  of  monomolecular 
reaction,  71 
for  determination  of  body  surface, 

518 
relation  of  mass  of  catalyzer  to  reac- 
tion constant,  75 
Equilibrium   in  reaction  of  bimolecular 
order,  72 
in  reaction  system,  77 
in  system  of  fermentation,  8 
relation  of  catalyzer,  75 
Erepsin,  digestion  in  vitro,  117 
in  intestinal  secretion,  169 
Esters,  formation  by  ferment  action,  86 
hydrolysis  of,  62 
racemic,  fermentation  of,  109 
Ether,  formation  of,  from  alcohol,  101 
Ethyl  acetate,  hydrolysis  of,  62 


548 


INDEX 


Ethyl  alcohol,  product  of  combustion  of 

lactic  acid,  263 
Exhalation   of  water,   relation   to   heat 

dissipation,  522 
Exogenous  ferments  in  alimentary  tract, 
169 
intoxication,  461 

protein,  elimination  of  end  products 
of,  418 
External  temperature,  relation  to  heat 
dissipation,  522 
to  metabolism.  471 


Fasting,  blood  in,  488 
body  weight  in,  488 
carbohydrate,  490 

metabolism,  484,  487 
fat  metabolism  in,  484,  487 
heat  production  in,  484 
muscular  work  in,  487 
partition  of  urinary  nitrogen,  486 
protein  metabolism  in,  484,  485 
respiratory  quotient  in,  487 
total,  483 

wasting  of  organs  in,  488 
Fat,  alimentary  secretions  in  feces,  215 
anabolism  of,  346 
caloric  equivalents  of,  513 

value  of,  24 
cleavage  in  intestine,  relation  of  bile, 

180 
combustion  of,  351 

in  diabetes,  327 
content  of  feces,  215 
catabolism  of,  350 
derivation  of  sugar  from,  240 
description  of,  23 
formation  from  glucose,  258,  358 
chemistry  of,  260 
in  diabetes,  311 
variations  in  disease,  259 
from  protein,  356 
from  sugar,  326,  343,  355 
relation   to   glucose   concentra- 
tion of  blood,  259 
hydrolysis  of,  351 
ingested  in  diet,  242 
intestinal    digestion    in    absence    of 

bile,  182 
metabolism,  342 
chart  of,  358 
in  fasting,  484,  487 
pathology  of,  358 
of  diet  in  stools,  215 
protein  complex,  347 
ration  in  diet,  500 
reciprocal  relation  to  carbohydrate 

in  diet,  476,  477 
resorbed,    route    of    transmission, 

197 
respiratory  quotient,  513,  516 


Fat,  respiratory  quotient  of  combustion 
of,  in  diabetes,  339 
saving  power  for  protein,  478 
site  of,  formation  of,  259 
soluble  state  of,  345 
source  of  acetone  bodies,  361 

in  body,  342 
starvation,  491 
state  of,  in  blood,  34 

in  thoracic  duct,  344 
synthetized  in  body,  342 
unsplit,  resorption  of,  196 
Fats,  bacterial  action  on,  in  alimentary 
canal,  218 
resorption  of  products  of,  digestion 

of,  196 
solution  of,  in  intestine,  relation  to 
bile,  180 
Fattening,  relation  to  protein  diet,  507 
Fatty  acids,  combustion  of,  351 
in  feces,  215 

oxidation  of,  328,  385,  397 
relation  of  bile  to  resorption  of, 
180 
degeneration,  356 
infiltration,  356 

of  liver,  in  phloridzin  intoxica- 
tion, 290 
organs,  fat  content  of,  356 
Feces,  208 

amino-acids  in,  214 

aromatic  bodies  of,  221 

bacteria  of,  212 

bile  in,  216 

biliary  acids  in,  174 

color  of,  216 

content  of  cholesterol,  350     • 

fat  content  of,  215 

fatty  acids  in,  215 

in  starvation,  213 

mass  of,  208 

nitrogen  content  of,  212,  417 

odor  of,  211 

peptids  in,  214 

phosphorus  in,  460 

protein  in,  213 

purin  of,  447 

bases  in,  433 
reaction  of,  211 

residue  of  alimentary  secretion  in, 
213,  216 
of  digestible  food,  212 
soaps  in,  215 
solids  of,  212 
sulphur  content  of,  421 
trypsin  in,  163 
urea  elimination  in,  404 
Feeding,  forced,  492 

with  protein,  387 
Ferment    action,  qualitative    specificity 
of,  111 
reversion  of,  85 
specificity  of,  104 
theory  of,  55 


INDEX 


549 


Ferment,  chemical  nature  of,  94 

concentration  of,  in  fermentation,  82 

hydrolysis  of  starch,  120 

inactivation  of,  76 

oxidation,    in   combustion   of   fatty 
acids,  355 

proteolytic,  intracellular,  388 

reaction,  reversion  of,  81 
Ferments,  exogenous  in  alimentary  tract, 

169 
Fermentation,  application  of  the  laws  of 
catalysis  to,  70,  77 

chemical  reactions  of,  56 

general  features  of,  68 

modus  operandi  of,  94 

of  carbohydrates  in  alimentary  tract, 
218 

of  fat  in  alimentary  tract,  218 

of  racemic  acids,  109 

of  stereoisomeric  hexoses,  108 

of  synthetic  methyl  glucosids,  109 
peptids,  109 

relation  to  ionization,  103 

theory  of  intermediary  reactions,  95 
Fever,  526 

conduction   and  radiation   of  body 
heat  in,  531 

cutaneous  circulation  in,  532 

cytolytic,  527 

heat  dissipation  in,  530 
production  in,  527 

hyperthermia  in,  527 

in  children,  533 

microorganismal,  527 

neurogenic,  527 

nitrogen  elimination  in,  530 

perspiration  in,  530,  532 

physiological,  526 

protein  catabolism  in,  480 
metabolism  in,  529 

relation  to  combustion  in  diabetes, 
302 

vasoconstriction  in,  532 
Filtration  of  proteins,  26 
Flesh  diet,  491 
Fleshening,  480,  507 
Food,  bulk  of,  in  intestine,  200 
Foods,  specific  dynamic  action  of,  469 
Foodstuffs,  bacterial  action  on,  217 

composition  of,  17 

conservation  of,  49 

definition  of,  17 

discussion  of,  48 

inorganic  constituents  of,  49 

relation  to  complete  diet,  49 

source  of,  in  relation  to  utilization,  49 

specific  dynamic  action,  510 

tables  of,  50,  51,  52,  53 
Forced  feeding,  492 
Formaldehyd,  addition  to  amino-acids,  31 

origin  by  condensation  of  CO2  and 
H20,  65 

oxidation  by  hydrogen  peroxid,  65 
Formate,  hydrolysis  of,  63 


Formic  acid,  combustion  of,  353 

origin  from  formaldehyd,  65 
Fright,  glucosuria,  283 
Fructose,  235 

toleration  in  diabetes,  303 
Fructosuria,  alimentary,  235,  280 

diabetic,  235,  308 

hepatic,  235 

idiopathic,  235 

varieties  of,  235 


Galactase,  190 
Galactose,  233 

anabolism  of,  234 

conversion  into  glucose  in  intestinal 
wall,  190 
in  liver,  190 
in  milk,  233 
in  mucin,  234 
in  nervous  system,  234 
in  tissues,  233 
Galactosuria,  233 

alimentary,  233 
Gastric  secretion,  126 

amylase  in,  145 
cephalogenous,  127 
cerebrospinal,  128 
endogenous,  127 
hydrochloric  acid  in,  129 

chemical    relation    of, 

132 
formation  of,  130 
influence  on  mastication  in,  126 
of  mock  feeding,  127 
of  special  senses,  127 
lactase  in,  145 
lipase  in,  116,  145 
maltase  in,  145 
mucus  of,  149 
saccharase  in,  145 
total  relations  of,  to  foods,  128 
variations  in  hydrochloric  acid 

in  disease,  135 
water  of,  147 
Gastro-intestinal  acetone  complex,  363 

bacterial  intoxication,  461 
Gelatin,  utilization  of,  378,  379 
Gelification  of  proteins,  27 
Gestation,  metabolism  in,  502 
Glands,  purin  content  of,  446 
Gliadin,  utilization  of,  379 
Glucosamin,  38,  236,  391 
Glucose,  21 

amount  in  circulatory  fluids,  245 
chemical  state  in  circulatory  fluids 

and  tissue,  244 
cleavage  into  lactic  acid,  263 
into  methyl  glyoxal,  263 
combustion  of,  in  diabetes,  297 

relation  to  adrenal  bodies,  265 
to  pancreas,  264 


550 


INDEX 


Glucose,  combustion  of,  without  oxygen, 
265 
concentration  in  blood,  252 
derivation  from  amino-acids,  385 
from  alanin,  391 
from  aspartic  acid,  393 
from  glutamic  acid,  392 
from  glycerose,  392 
from  glycocoll,  391 
from  lysin,  391 
from  serin,  392 
direct  oxidation  of,  261 
fat  formation  from,  258 
fermentation  of,  59 
from  lactic  acid,  392 
formation  from  amino-acids,  390 

relation  to  specific  dynamic 
action  of  protein,  476 
from  fat,  326 

in  diabetes,  322,  324 
from  glycerol  in  diabetes,  323 
from  protein,  curve  of,  393 
quantitative,  394 
in  diabetes,  origin  of,  313 
indirect  oxidation  of,  263 
lipoids,  244 
nitrogen  ratio,  316,  318,  394 

in  phloridzin  intoxication, 
319 
overproduction  of,  in  diabetes,  306 
protein,  244 
relation  to  creatin,  480 

to  combustion  of  butyric  acid, 

368 
to  lactic  acid  in  diabetes,  298 
source  in  phloridzin  intoxication,  289 
of  fat,  355 
of  glycerol,  344 
Glucosids,  definition  of,  22 
hydrolysis  of,  61 

synthetic  methyl,   fermentation  of, 
109 
Glucosuria,  276,  287 
alimentary,  280 
due  to  epinephrin,  285 

to  excess  of  muscular  glycolysis, 

286 
to  excessive  hepatic  glycolysis, 

283 
to    failure    in    combustion    of 
glucose,  287 
in     muscular    gycogenesis, 
286 
to  lowered  hepatic  glycogenesis, 
281 
hemic,  276,  287 

in  diabetes,  relation  to  diet,  325 
renal,  276,  287 
saline,  284 
Glucothionic  acid,  236 

combustion  in  diabetes,  306 
Glucuronic  acid,  269 

alimentary,  270 
combustion  in  diabetes,  306 


Glucuronic  acid,  conjugated  with  phenols, 
219 
conjugations  of,  269 
derivation  of,  270 
from  glucose,  262 
in  disease,  270 
d-Glucuronic    acid,    possible    source    of 

pentose,  232 
Glucuronuria,  262 
Glutamic  acid,  35 

in  oxyproteic  acid,  389 
source  of  glucose,  392 
Glutamin,  35 

Glyceric  acid,  glucose  formation,  392 
in  formation  of  glycerol,  344 
source  of  glycerol,  274 
Glycerids,  melting  point,  34 
Glycerol,  273 

combustion  of,  351 
conversion  into  glucose,  274 

into  sugar,  328 
derivation,  for  formation  of  fat,  275 
from  amino-acids,  273 
from  glucose,  273 
fate  of,  in  body,  274 
formation  from  glucose,  344 
Glycerol-phosphoric  acid,  348 
Glycerose,  glucose  formation,  392 
in  formation  of  glycerol,  344 
source  of  glycerol,  274 
Glycocoll,  32 

catabolism  of,  408 
in  bile,  173 
in  blood,  408 
in  hippuric  acid,  408 
in  urine,  396,  417 

origin  of,  for  conjugation  to  hippuric 
acid,  227 
in  decomposition  of  purin,  408 
oxyproteic  acid,  389 
source  of  glucose,  391,  393 
synthesis  of,  378 
in  body,  408 

on    administration    of    benzoic 
acid,  408 
Glycogen,  247 

combined  in  tissues,  248 
combustion  of,  254 
content  of  muscle,  253 
conversion  into  glucose,  254 
formation  of,  247 
in  liver,  249 
free  in  tissues,  248 
in  blood,  252 

of  liver,  derivation  from  food,  248 
relation   to   portal   hypergluco- 
emia,  249 
relations  in  diabetes,  304 
transportation  of,  252 
Glycogenase,  254 

Glycogenesis,  hepatic,  relation  to  gluco- 
suria, 281 
Glycogenuria  in  diabetes,  308 
Glycol,  source  of  cholin,  348 


INDEX 


551 


Glycolysis,  following  Bernard  puncture, 

249 
Goitre,  oxidation  in,  537 
Gout,  455 

alkalinity  of,  blood  in,  458 

blood  content  of  uric  acid,  455 

catabolism  of  exogenous  purins  in, 
455 

purin  catabolism  in,  455 
elimination  in,  457 

toxic  manifestations  in,  458 

urate  depositions,  457 

uricolysis  in,  456 
Growth,  law  of,  504 
Guanidin,  423 

Guanin,  conversion  into  hypoxanthin,  67 
into  xanthin,  440 

structure  of,  432 
Guanosin,  430 
Guanylic  acid,  occurrence  of,  437 


Hair,  nitrogen  content  of,  417 

relation  to  heat  dissipation,  519 
Hemoglobin,  anabolism  of,  377 
Hematoporphyrin,  465 
in  urine,  417 
relation  to  bilirubin,  176 
Heat  dissipation  in  fever,  530 

relation  to  air  currents,  524 
to  circulation  of  skin,  520 
to  clothing,  525 
to  exhalation  of  water,  522 
to     external     temperature, 

523 
to  hair,  519 
to  humidity,  523 
to  perspiration,  521 
to  skin,  520 

to  subcutaneous  fat,  521 
of  specific  dynamic  action,  510 
output,  table  of,  512 
production,  basal,  509 
in  diabetes,  340 
in  fasting,  485 
in  fever,  527 
in  gestation,  503 
in  infancy,  504 
in  metabolism,  514 
of  chemical  regulation,  510 
of  foodstuffs,  470 
of  muscular  contraction,  511 
per  unit  surface,  518 
relation  to  metabolism,  512 
relations  in  digestion,  206 
Helicin,  hydrolysis  of,  61 
Hematin  relation  to  tryptophan,  220 

structure  of,  176 
Hepatic  glycogen,  derivation  of,  248 

glycogenesis,  in  diabetes,  309,  310 
Heptargia,  282 
Heterogeneous  system,  catalysis  in,  87 


Hexoses,  fermentation  of,  108 
Hippokoprosterin,  350 
Hippuric  acid,  225 

formation  in  kidney,  227 
hydrolysis  of,  62 
in  urine,  417 

relation  to  vegetarian  diet, 
227 
origin  in  intestine,  226 
in  metabolism,  226 
Histidin,  34 

catabolism  of,  416 
source  of  aceto-acetic  acid,  360 
of  acetone,  359 
His  ton,  nucleic  acid,  429 
Homogentisic  acid,  410 
Humidity,  relation  to  heat  dissipation, 

523 
Hydrazin,  reactions  of,  112 
Hydrochloric  acid,  chemical  relations  in 
gastric  secretion,  132 
formation  of,  in  stomach,  130 
in  gastric  secretion,  129 

action  on  secretion  of 

ferments,  132 
activation  of  pepsino- 
gen, 132 
free  and  combined,  134 
quantitative  secretion, 

133 
relation  of  secretion  to 
diet,  134 
to    peptic    diges- 
tion, 132 
variations    in    disease, 
135 
relation  to  peptic  digestion,  140 
Hydrogen  peroxid,  oxidation  of,  65 

relation  to  formation  of  formal- 
dehyd,  65 
Hydrolytic  cleavage,  60 

fermentation,  60 
Hydroquinon,  derivation  from  tyrosin  in 
intestine,  219 
oxidation  to  quinon,  63 
Hydroxylamin,  hydrolysis  of,  112 
para-Hydroxy-phenyl-pyruvic  acid,  411, 

412 
Hyperammonuria,  primary,  407 

secondary,  407 
Hypercapnia,  glucosuria,  285 
Hyperglucemia  in  diabetes,  306 

relation    to  glucosuria   in    diabetes, 
307 
Hyperpurinemia,  alimentary,  454 

in  gout,  458 
Hypophysis,    relation    to    carbohydrate 

metabolism,  297 
Hypoxanthin,   conversion   into  xanthin, 
439 
derivation  from  adenin,  439 
origin  from  guanin,  67 
oxidation  to  xanthin,  64 
structure  of.  432 


552 


INDEX 


Imbibition,  factor  in  intestinal  resorp- 
tion, 202 
Iminazol-pyruvic  acid,  416 
Inactivation  of  ferment,  76 
Inanition,  482 

elimination  of  creatin  in,  427 
protein  catabolism  in,  497 
Indol  acetic  acid,  derivation  from  trypto- 
phan in  intestine,  220 
derivation  from  tryptophan,  220 
propionic  acid,  derivation  from  tryp- 
tophan in  intestine,  220 
Indoxyl,  derivation  from  tryptophan  in 
intestine,  220 
relation    to    total    conjugated    sul- 
phates, 221 
Induction,   theory  of,   in  catalysis  and 

fermentation,  97 
Infancy,  food  requirements  in,  504 
heat  production  in,  504 
metabolism  in,  504 
nutrition  in,  502 
Infections,  acidosis  in,  362 

lag  in  nitrogen  elimination,  419 
peptone  elimination  in,  389 
protein  metabolism  in,  529 
Inosin,  430 
Inosinic  acid,  occurrence  of,  437 

source  of  hypoxanthin,  443 
of  uric  acid,  443 
Iodin,  combination  with  hydrogen,  58 
Ionization,  relation  to  fermentation,  103 
Intermediary    reactions,    theory    of,    in 

catalysis  and  fermentation,  95 
Intestinal  contents,  alkalinity  in,  154 
digestion,  in  absence  of  pancreatic 
juice,  164 
pepsin  in,  141 
mucosa,  digestion  of  nucleotid  in,  434 
putrefaction,     relation    to    urinary 

aromatic  bodies,  221 
secretion,  alkali  in,  167 
ferments  of,  168 
mucus  in,  167 
of  pancreas,  166 
relation  to  digestion,  167 
water  of,  167 
Intestine,  digestion  in,  153 

formation  of  urobilinogen  and  uro- 
bilin from  bilirubin,  176 
resorption  from,  187 
Intra-intestinal  pressure  factor  in  intes- 
tinal resorption,  202 
Invertase  in  succus  entericus,  115 

pancreatic  secretion,  158 
Isodynamic  law,  512 
Isomerism,  of  proteins,  44 


Jaundice  464 


b-KEPHALIN,  349 

Ketohexoses,  description  of,  21 
Ketones,  C5C160,  58 
Ketonic  intoxication,  465 
Ketonuria  in  diabetes,  330 
Ketoses,  definition  of,  18 
Ketosis,  359 

chart  of,  367 
Kidney,  elimination  of  urea  in,  404 

fatty  degeneration  of,  357 
Kilogrammeter,  unit  of  work,  538 
Koprosterin,  350 
Kynurenic  acid,  413 


Lactase  in  intestinal  secretion,  168 
in  pancreatic  secretion,  115,  158 
in  succus  entericus,  115 
salivary,  126 
Lactation,  metabolism  of,  503 
Lactic  acid,  266 

bacterial,  268 

cleavage    into    C02    and    ethyl 

alcohol,  263 
conversion  into  butyric  acid,  343 

into  uric  acid,  445 
derivation     from     amino-acids, 
268 
from  carbohydrates,  267 
from  glucose,  263 
formation  of,  265 
in  asphyxia  and  disturbances  in 

oxidation,  269 
in  diabetes,  269,  305 
in  hepatic  disease,  269 
in  urine  in  phosphorus  poison- 
ing, 396 
origin  from  alanin,  395 
source  of  glucose,  392 
of  glycerol,  274,  344 
Lactose  in  metabolism,  243 
Lactosuria,  alimentary,  280 

lactational,  243 
Lag  in  nitrogen  elimination,  418 

in  protein  catabolism,  419 
Langerhans,     islands     of,     relation     to 

pancreatic  diabetes,  294 
Law  of  isodynamic  relations,  512 
Lead   poisoning,   blood   content  of  uric 

acid,  455 
Lecithin,  348 
Leucin,  35 

in  oxyproteic  acid,  389 

in  urine,  396 

source  of  acetone,  359 

of  b-oxy-butyric  acid,  359 
of  glucose,  393 
Leukemia,  blood  content  of  uric  acid  in, 
455 
elimination  of  peptone  in,  389 


INDEX 


553 


Leukemia,  nucleic  catabolism  in,  454 
Levulose,  235 

conversion  into  glucose  in  intestinal 
wall,  190 
in  liver,  191 
Lipase  in  gastric  secretion,  116,  145 

variations  in  disease,  146 
in  intestinal  secretion,  169 
in  pancreatic  secretion,  116,  159 
Lipemia  in  diabetes,  335 
Lipoid,  relation  to  law  of  partition,  347 
Lipoids  of  bile,  178 

relation  to  semipermeability  of  cell 

membrane,  347 
sebaceous,  349 
Liver,  amino-acids  in  urine  in  diseases  of, 
396 
antagonism  .of  fat  and  glycogen,  251 
arginase  in,  396 
combustion  in,  255 
degeneration,  nucleic  catabolism  in, 

454 
disease,   influence   on   carbohydrate 

and  protein  metabolism,  480 
fatty  degeneration  of,  357 

infiltration  of,  357 
formation  of  glycogen,  249 

of  urobilin  in  aseptic  autolysis 
of,  177 
relation  to  nucleic  catabolism,  437 
storage  capacity  for  glycogen,  varia- 
tions in  disease,  257 
Lungs,  oxidation  in  diseases  of,  535 
Lysin,  37 

catabolism  of,  415 
source  of  cadaverin,  415 

of  glucose,  391 
synthesis  of,  378 


M 


Malic  acid,  fermentation  of,  59 
Malignant  neoplasms,  oxidation  in,  537 
Maltase  in  pancreatic  secretion,  115,  158 

in  succus  entericus,  115,  168 

salivary,  124 
Malted  liquors,  purin  content  of,  446 
Maltose  in  metabolism,  242 
Maltosuria,  alimentary,  242 

diabetic,  243,  308 
Mass  of  diets,  181 

of  tissue,  relation  to  metabolism,  468 
Masses  of  diets,  standard  and  various,  183 
Mastication,  imperfect,  result  to  diges- 
tion, 204 

influence  on  gastric  secretion,  126 
Melting  point  of  fats,  24 
Melituria,  276 

alimentary,  271,  280 

mixed,  in  diabetes,  308 

relation  of  liver  to,  308 
Mental  work,  thermic  equivalent,  539 
Metabolism  at  high  altitude,  541 


Metabolism,  carbohydrate,  230 

carbon  dioxid  elimination,  514,  515 
considered  as  whole,  468 
O-consumption,  514,  515 
general  considerations,  228 
heat  production  in,  514 
in  childhood,  505 
in  gestation,  502 
in  infancy,  504 
in  obesity,  508 
in  old  age,  505 
in  overnutrition,  506 
in  undernutrition,  505 
of  creatin-creatinin,  423,  469 
of  fat,  342 
of  lactation,  503 
of  protein,  370,  469 
of  purin,  428,  469 
of  sulphur,  420 
oxidation  in,  534 

relation  to  external  temperature,  471 
to  heat  production,  512 
to  mass  of  tissue,  468 
to  work,  538 
respiratory  quotient,  514,  515     v 
suboxidation  in,  534,  535 
superoxidation  in,  534 
total  in  diabetes,  339 
with  work,  539 
Metals,  oxidation  of,  64 
Methylguanidin  acetic  acid,  423 

in  urine,  417,  426 
Methylimidazol,  synthesis  of,  436 
Methylpurins,  oxidation  of,  446 
Methylpyridyl  ammonium  in  urine,  225 
Milk  diet,  mass  of,  183 

production,  relation  to  diet,  503 
protein  content  of,  496 
Mixed  diet,  mass  of,  184 
Mock  feeding,  influence  on  gastric  diges- 
tion, 127 
Monochloracetic  acid,  hydrolysis  of,  63 
Motor  functions   of   digestion,    disturb- 
ances  due   to   abnormalities, 
204,  205 
of  stomach,  150 

variations  in  disease,  151 
Mucin,  anabolism  of,  377 

galactose,  content  of,  234 
in  urine,  417 
Mucus  in  gastric  secretion,  variation  in 

disease,  149 
Muscle,  autolysis  of,  424 

functions  of  combustion,  255 
purin  content  of,  446 
Muscles,  formation  of  glycogen  in,  253 
glycogen  content  of,  253 
site  of  combustion  of  glucose,  255, 
256 
Muscular  contraction,  heat  of,  511 

degeneration,  elimination  of  creatin 

in,  427 
gly oogenesis  and  glycolysis  in  dia- 
betes, 311 


554 


INDEX 


Muscular  work  in  fasting,  487 

relation  to  purin  output,  443 
supported  by  fat,  256 
by  protein,  25 

Myxedema,  oxidation  in,  536 


N 


Nails,  nitrogen  content  of,  417 
Narcosis,  acetone  complex  after,  364 
Narcotics,  glucosuria,  284 
Neoplasms,  nucleic  catabolism  in,  454 

peptone  elimination  in,  389 
Nephritis,  blood    content  in    uric    acid, 
455 
lag  in  nitrogen  elimination,  419 
Neurin,  relation  to  cholin,  349 
Neutral  sulphur  in  urine,  414,  417 
Nitrobenzol,  reduction  to  anilin,  67 
Nitrogen  balance,  418 
content  of  feces,  212 
cutaneous  elimination,  464 
elimination,  in  fever,  530 

influence  of  carbohydrate,  419 
lag  in,  418 
in  perspiration,  417 
rest  in  urine,  416 
retention,  419 

urinary,  partition  in  fasting,  486 
Nitrogenous  bodies  in  bile,  178 

end  products  in  urine,  relation   to 
uremia,  465 
Normal  diet,  493 

Nucleic  acid,  anabolism  of,  434,  436 
hydrolysis  of,  439 
metabolism  of,  434 
pathological  variations  in  anab- 
olism, 438 
resorption  of,  433 
structure  of,  428 
metabolism  of  different  tissues,  443 
relation  to  work,  540 
specificity  of,  442 
Nuclein,  429 

Nucleinase,  432,  433,  439 
Nucleoprotein,  428 

digestion  of,  432,  436 
tryptic  digestion  of,  433 
Nucleosid,  anabolism  of,  436 
bacterial  cleavage,  433 
cleavage  in  intestinal  wall,  434 
digestion  of,  432 
resorption  of,  433 
structure  of,  429 
varieties  of,  430 
Nucleosidase,  439 
Nucleotid,  anabolism  of,  436 

cleavage  in  intestinal  wall,  434 
digestion  of,  432 
resorption  of,  433 
structure  of,  429 
Nucleotidase,  432,  433,  439 
Nutrition  in  infancy,  502 


Oatmeal,  toleration  in  diabetes,  303 
Obesity,  508 

masked  diabetes,  311 
oxidation  in,  536 
Oleic  acid,  combustion  of,  354 
Order  of  reaction,  relation  to  catalyzer,  75 
Organs,  wasting  in  fasting,  488 
Ornithin,  35 

catabolism  of,  415 
origin  from  arginin,  396 
source  of  putrescin,  415 
Overnutrition,  506 
Oxalic  acid,  272 

.    alimentary,  272 
endogenous,  272 
origin  from  carbohydrate,  272 
from  creatin,  272 
from  glycocoll,  272 
from  purin,  273 
relation  to  urea,  449 
Oxaluria,  273 
Oxydase,  534 

O-absorption  in  diabetes,  340 
O-consumption  in  metabolism,  514,  515 
Oxidation  fermentation,  63 
ferments,  534 

in  combustion  of  fatty  acids,  353 
in  anemia,  536 
in  cardiac  disease,  536 
in  castration,  536 
in  diabetes,  536 
in  diseases  of  lungs,  535 
in  exophthalmic  goitre,  537 
in  malignant  neoplasms,  537 
in  metabolism,  534,  535 
in  myxedema,  536 
in  obesity,  536 
in  sepsis,  537 
in  shock,  536 
of  products  of  protein  catabolism, 

396 
of  purin  bases,  439 
of  uric  acid,  448 
relation  to  oxygen,  535 
O-phenyl-ethylamin,      derivation      from 

tyrosin  in  intestine,  221 
p-Oxy-phenyl-acetic  acid,  derivation  from 

tyrosin  in  intestine,  219 
p-Oxy-phenyl  lactic  acid,  410 
p-Oxy-phenyl-propionic  acid,  derivation 

from  tyrosin  in  intestine,  219 
Oxyproteic  acid,  388 
in  urine,  417 
Ozone,  relation  to  formation  of  formalde- 
hyd,  65 
to  oxidations  in  body,  534 


Pancreas,  internal  secretion  of,  166 
relation  to  diabetes  296 


INDEX 


555 


Pancreas,  relation  to  sugar  combustion, 
264 
secretion  of,  153 
self-digestion   of,    165 
Pancreatic  diabetes,  formation  of  glucose 
from  amino-acids,  390 
digestion  of  starch  in  vitro,  115 
juice,  toxicity  of,  467 
secretion,  amylase  in,  115,  157 
chymosin,  160 
digestion  in  intestine  in  absence 

of,  164 
emulsin,  159 
in  stomach,  146 
invertase  in,  158 
lactase  in,  115,  158 
lipase  in,  116,  159 
maltase  in,  115,  158 
pathology  of,  163 
relations  to  gastric  secretion,  153 
trypsin,  160 
variations  in,  154 
Paraldehyd,  origin  from  aldehyd,  57 
Pentamethy  lendiamin  (cadaverin)  ,415 
Pentose,  231 

content  of  tissues,  231 
conversion  into  glucose  in  intestine, 
191 
Pentoses,  description  of,  20 
Pentosuria,  467 

alimentary,  231 
idiopathic,  231 
in  diabetes,  309 
nucleic,  231 
Pepsin,  action  within  intestinal  tract,  141 
on  nucleosid,  432 
on  polynucleotid,  432 
digestion  in  vitro,  116 
in  gastric  secretion,  138 
relation  to  hydrolysis  of  protein,  138 
Pepsinogen,  138 

Peptic  digestion,  amino-acids  in,  139 
peptones  in,  138 
proteoses,  138 

relation    to    hydrochloric    acid, 
140 
to  tryptic  digestion,  139 
variation  in  disease,  141 
Peptid,  40 

binding,  39 
in  urine,  417 
Peptids  in  feces,  214 
resorption  of,  192 
synthetic,  48 

fermentation  of,  109 
Peptone,  elimination  in  infections,  389 
in  leukemia,  389 
in  neoplasms,  389 
in  peptic  digestion,  138 
resorption  of,  192 
Peristalsis,  209 

influence  of  bile,  179 
Peroxydase,  534 
Perspiration  in  fever,  530,  532 


Perspiration  nitrogen  content,  417 

relation  to  heat  dissipation,  521 
Phenylacetic    acid,     derivation    from 

phenylalanin  in  intestine,  219 
Phenylaceturic  acid,  219 
Phenylalanin,  32 

catabolism  of,  409,  410,  411,  412 
combustion  of,  in  body,  219 
in  oxyproteic  acid,  389 
oxidation  of,  391 
putrefaction  of,  in  intestine,  219 
source  of  aceto-acetic  acid,  360 

of  acetone,  359 
synthesis  of,  378 
Phenylethylamin,  derivation  from  phenyl- 
alanin, in  intestine,  221 
Phenyl  lactic  acid,  410 
Phenylpropionic    acid,    derivation    from 

phenylalanin  in  intestine,  219 
Phenol,  conjugation  with  sulphuric  acid, 
219 
derivation  from  tyrosin  in  intestine, 
219 
Phenols,  conjugated  with  glucuronic  acid, 

219 
Phloridzin,  acidosis  in,  362 
glucosuria,  287 

intoxication,  formation  of  glucose 
from  amino-acids,  390 
C  :  N  ratio,  319 
Phosphatid,  347 

catabolism  of,  350 
in  urine,  417 
Phosphorus  balance  in  metabolism,  460 
compounds  in  bile,  178 
elimination  of,  460 
cutaneous,  460 
glucosuria,  284 
in  feces,  460 

influence  of  Ca  and  Mg  on  elimina- 
tion, 460 
in  urine,  460 
metabolism  of,  459 
poisoning,  acidosis  in,  364 

source  of  fat  in  tissues  in,  357 
Physical  regulation  of  body  temperature, 

519 
Pneumonia,  autolysis  in,  389 

oxidation  in,  535 
Polynucleotid,  equation,  431 

structure  of,  429 
Polysaccharids,  definition  of,  22 
Precipitation  of  proteins,  28 
Production  of  body  heat,  509 
Products  of  reaction,  concentration  of,  73 
Prolin,  35 

source  of  glucose,  393 
Protamin,  construction  of,  43 

formation  by  ferment  action,  87 
nucleic  acid,  429 
synthesis  of,  in  milk,  376 
Protein,  amphoterism,  27 
anabolism  of,  373 

pathological  variation  in,  382 


556 


INDEX 


Protein,  anabolism  of,  special,  377 
assimilation  of,  370 
blood  plasma,  synthesis  of,  372 
caloric  equivalents  of,  513 

value  of,  48 
catabolism  of,  383 

chart  of,  420 

in  fasting,  385 

in  fever,  480 

in  inanition,  497 

oxidation  of  end   products  of, 
396 

the  elimination  of  end  products, 
417 
chemistry  ol,  30 
coagulation,  28 
colloidal  nature  of,  24 
concentration  in  blood,  384 
•    concept  of  molecule  of,  44 
construction  of,  45 

of  molecule,  42 
content  in  amino-acids,  38 

in  milk,  490 
crystallization,  27 
degradation  of,  45 
denaturation,  29 
derivation  of  sugar  from,  237 
diet,  491 

mass  of,  183 
digestion  by  trypsin,  161 
endogenous  catabolism  of,  388 

hydrolysis  of,  386 
equilibrium  between  cells  and  fluids, 

387 
excessive  input,  498 
exogenous  catabolism  of,  388 

hydrolysis  of,  387 
filtration  and  diffusion,  26 
forced  feeding  with,  387 
fuel  for  work,  540 
gelification,  27 

heat  value  of,  in  diabetes,  326 
hydrolysis  of,  61,  385 

by  pepsin,  138 

in  organism,  385 
in  diet,  493 
in  feces,  213 

incomplete  utilization  of,  379 
isomerism  in,  44 
metabolism  of,  370,  469 

chart  of,  453 

in  diabetes,  313 

in  fasting,  484,  485 

in  fever,  529 

in  gestation,  502 

in  work,  540 

relation   to   purin   metabolism, 
442,  444 
minimal  ration,  498 
molecular  weight,  24 
molecule,    schematic   representation 

of,  48 
needs  for  anabolism,  496 
origin  in  plants,  29 


Protein  overfeeding,  507 
plant,  availability,  500 
precipitations,  28 
ration,  statistical,  494 
relation  to  fat  and  carbohydrate  in 

diet,  476 
requirement  in  diet,  494,  497,  499 
resorption  of,  192,  370 
respiratory  quotient,  513,  516 

of  combustion  in  diabetes, 
336,  337 
saving  power  of  fat  and  sugar,  476, 

481 
solutions,  tension  of,  27 
source  of  acetone  bodies,  359 
of  glucose  in  diabetes,  315 
of  purin,  382 
special,  formation  of,  381 
specific  dynamic  action  of,  469 
storage  of,  387 
sugar  content,  38 

utilization    in    sprouting    of    plant 
seeds,  375 
Proteins  in  bile,  171 

biuret  reaction  of,  31 
conjugated,  380 
description  of,  24 

relations  to  hydrolysis,  381 
putrefaction  in  alimentary  tract,  218 
Proteolytic  ferment,  intracellular,  388 
Proteose  in  peptic  digestion,  138 
Protoplasm,    physico-chemical    constitu- 
tion of,  factor  in  intestinal  resorption, 
202 
Putrefaction  of  phenylalanin  in  intestine, 
218 
of  protein  in  alimentary  tract,  218 
of  tryptophan  in  intestine,  220 
of  tyrosin  in  intestine,  218 
Purin,  anabolism  of,  435,  454 
bases,  in  feces,  433 
in  urine,  445 
oxidation,  439 
relation  to  fever,  465 
to  uric  acid,  449 
state  of  circulation,  450 
catabolism,  excessive,  454 

in  gout,  455 
content  of  blood,  446 
of  cocoa,  446 
of  coffee,  446 
of  glands,  446 
of  malted  liquors,  446 
of  muscle,  446 
of  tea,  446 
of  vegetables,  446 
deaminization  of,  in  liver,  437 
elimination  in  gout,  457 
endogenous,  442,  445 
exogenous,  442,  445 
utilization,  437 
extranuclear  derivation  of,  443 
-free  diet,  445 
metabolism,  428,  469 


INDEX 


557 


Purin  metabolism,  chart  of,  452,  453 
pathology  of,  454 
relations  to  protein  metabolism, 

442,  444 
test  of,  459 
nucleosid,  430 
nucleus,  432 
output,  curve  of,  449 
in  starvation,  444 
relation  to  muscular  work,  443 
relation  to  urea,  449 
resorption  of,  433 
synthesis  of,  436 

from  protein,  382 
total  oxidation  of,  441 
Purins,  endogenous,  catabolism  of,  447 
exogenous,  catabolism  of,  447 
of  feces,  447 

relation  of  urinary  purin  to  purin 
metabolism,  449 
Purity  of  reacting  substances,  77 
Putrescin,  derivation  from  ornithin,  415 
Pyrimidin,  anabolism  of,  435 
bases,  fate  of,  459 
nucleosid,  430 
relation  and  solubility  of  uric  acid, 

459 
resorption  of,  433 
ring,  431 

synthesis  from  protein,  382 
Pyrrol  ring,  in  bilirubin,  175 


Quinonoid  reaction,  411 


Reaction  of  fermentation,  measurement 

of,  80 
Reactions  of  fermentations,  56 
Reduction  fermentation,  66 
Regulation  of  body  temperature,  509,  517 
Renal  glucosuria  in  disease,  290 

in  phloridzin  intoxication,  288 
retention  of  sugar  in  diabetes,  307 
Rennet  in  gastric  secretion,  144 
Reptiles,  purin  output  in,  445 
Resorption,  defects  in,  results  on  diges- 
tion, 204,  205 
gastric,  149 
in  intestine,  187 
in  stomach,  186 
of  carbohydrate,  189 
of  fat,  196 

of  products  of  digestion,  186 
mechanism  of,  200 
of  protein,  192 
relation  of  mass  of  food  to 

velocity  of,  199 
space  relations,  199 
relation  to  feces,  214 


Respiration    apparatus,    metabolism    in, 
515 
heat  production  of,  510 
Respiratory  quotient,  516 

for  combustion  of  fat,  336 
of  glucose,  335 
of  protein,  336 
in  diabetes,  335 
in  fasting,  487 
in  metabolism,  514,  515 
in  mixed  diets,  516 
of  carbohydrate,  513 
of  fat,  513 
of  protein,  513 
Rest  nitrogen,  389,  416 
Reversion  of  ferment  action,  85 

reaction,  81 
Rotation  of  monosaccharids,  21 
d-Ribose,  231 
Ribose,  anabolism  of,  435 
in  nucleic  acid,  430 
resorption  of,  433 


Saccharase  in  intestinal  secretion,  168 

salivary,  126 
Saccharic  acid,  combustion  in  diabetes, 
306 
from  glucose,  262 
Saccharosuria,  alimentary,  242,  280 
Salicylic  aldehyd,  oxidation  to  salicylic 

acid,  63 
Salivary  digestion,  119 
amylase,  119 

pathological  variations  in, 
122 
in  vitro,  115 
maltase,  124 
saccharase,  lactase,  126 
Salmon,    growth   of  milt  in   migration, 

375 
Salts  in  diet,  493 

Saving  power  for  protein,  476,  481 
Seasonal  variation  in  body  weight,  507 
Sebaceous  lipoids,  349 
Secretin,  action  of,  155 
Secretion,  heat  production  of,  510 
Secretions,    digestive,    abnormal,    result 
on  digestion,  204,  205 
intestinal  residue  in  feces,  216 
Selenous  acid,  reduction  of,  66 
Senses,     special,     influence    on    gastric 

secretion,  127 
Sepsis,  nucleic  catabolism  in,  454 

oxidation  in,  537 
Serin,  33 

source  of  glucose,  392 
of  glycerol,  274 
of  lactic  acid,  268 
Shock,  oxidation  in,  536 
Side  reaction  in  catalysis,  100 
Sinigrin,  fermentation  of,  59 


558 


INDEX 


Skatol,   derivation  from   tryptophan   in 

intestine,  220 
Skin,  elimination  of  urea,  404 

relation  to  heat  dissipation,  520 
secretion  of,  464 
Soaps,  in  feces,  215 
Specific  dynamic  action  of  foodstuffs,  207, 

469 
Specificity  of  ferment  action,  104 
qualitative,  111 
quantitative,  104 
relation     to     intermediary 
reactions,  104 
Starch,  hydrolysis  of,  60 
of  ferment,  120 
Standard  ration,  protein,  494 
Starvation,  acidosis  in,  362 
fat,  491 
feces  in,  213 
protein,  489 
purin  output  in,  444 
Stearic  acid,  combustion  of,  351 
Stereoisomerism,  definition  of,  19 
Sterin,  349 
Stoicheiometric  relations  in  fermentation, 

102 
Stomach,  digestion  in,  126 
duodenal  contents  in,  146 
general  consideration  of  functions  of, 

152 
motor  functions  of,  150 
resorption  by,  149 
Subcutaneous  fat,  relation  to  heat  dissi- 
pation, 521 
Suboxidation  in  metabolism,  534,  535 
Substrate,  concentration  in  fermentation, 
78 
of  reaction,  initial  concentration  of, 
73 
Succus  entericus,  amylase  in,  115 

digestion  of  nucleosid,  433 
of  nucleotid,  433 
of  polynucleotid,  433 
erepsin  in,  117 
invertase  in,  115 
lactase  in,  115 
lipase  in,  115 
maltase  in,  115 
toxicity  of,  468 
Sugar,  colloidal,  244 

combined  in  tissues,  230 
concentration  in  blood,  relation  to 
combustion,  formation  of 
glycogen  and  fat,  246 
renal  level  of,  245 
content  in  protein,  38 
conversion  into  fat,  343 
derivation  from  fat,  240 

from  protein,  237 
free  in  blood,  244 
of  blood,  derivation  of,  237 
synthesis  of,  18 

by  chlorophyl,  18 
Sulphate  in  urine,  414 


Sulphate,  preformed  in  urine,  421 

relation  to  urinary  nitrogen,  421 
Sulphur  balance  in  metabolism,  422 

combined  in  metabolism,  421 

compounds  in  bile,  171 

conjugated  in  urine,  421 

dioxid,  oxidation  of,  58 

in  cystin,  421 

in  feces,  421 

in  oxyproteic  acid,  389 

in  perspiration,  414,  421 

inorganic  in  metabolism,  421 

in  urine,  421 

metabolism  of,  420 

neutral  in  urine,  414,  421 

relation  to  urinary  nitrogen,  422 
Sulphuric  acid,  conjugated,  219 

amount  per  diem,  221 
Superoxidation  in  disease,  537 

in  metabolism  534 
Surface  tension,  factor  in  intestinal  re- 
sorption, 202 


Tartronic    acid,    conversion    into    uric 
acid,  445 
in  formation  of  glycerol,  344 
source  of  glycerol,  274 
Taurin,  derivation  from  cystin,  414 
from  erythrocytes,  173 

in  bile,  172 
Tea,  purin  content  of,  446 
Tellurous  acid,  reduction  of,  66 
Temperature,  influence  on  reaction  velo- 
city, 74 
Tetramethylene  diamin  (putrescin),  415 
Theobromin,  446 
Theophyllin,  446 
Theory  of  ferment  action,  55 
/3-Thiolactic  acid,  414 
Thoracic  duct,  state  of  fat  in,  344 
Thymin,  conversion  into  uracil,  440 

occurrence  of,  437 

structure  of,  431 
Toleration  for  glucose,  relation  to  acidosis 

in  diabetes,  333 
Traumatism,  glucosuria,  283 
Trimethylamin,  348 
Triolein,  combustion  of,  354 
Trypsin,  action  on  nucleotid,  433 

digestion  in  vitro,  116 

in  feces,  163 

pancreatic  secretion,  160 

scope  of  digestion  of  proteins,  162 
Trypsinogen,  160 
Tryptic  digestion,  relation  to  preceding 

peptic  digestion,  140 
Tryptophan,  34 

catabolism  of,  409,  413 

protein  metabolism  without,  380 

putrefaction  of,  in  intestine,  219 
Tyrosin,  33 


INDEX 


559 


Tyrosin,  bacterial  action  on,  in  intestine, 
218 
catabolism  of,  409,  410,  411,  412 
combustion  in  body,  219 
in  urine,  396 
source  of  acetone,  359 
of  epinephrin,  413 
of  lactic  acid,  268 
synthesis  of,  378 
Tyrosinase,  fermentation  by,  107 
Tuberculosis,  autolysis  in,  389 


Undernutrition,  505 
Uracil,  derivation  from  thymin,  440 
in  urine,  459 
occurrence  of,  437 
origin  from  cytosin,  440 
structure  of,  431 
Urate,  bi-,  450 

deposition  in  tissues,  457 
mono-,  450 
quadra-,  450 
Urates,  reaction  of  solutions  of,  450 

solubility  of,  451 
Urea  ammonia,  elimination,  course  of,  417 
equilibrium,  405 
blood  content  of,  400 
cutaneous  elimination,  464 
derivation  from  arginin,  398 
from  creatinin,  426 
from  uric  acid,  441 
elimination  of,  400,  404 
endogenous,  402 

amount  of,  404 
exogenous,  402 

amount  of,  404 
formation  of,  398,  399 

from  ammonium  carbonate,  397 
from  creatinin,  400 
from  guanidin,  423 
from  uric  acid,  400 
outside  of  liver,  400 
hydrolysis  of,  62 
origin  from  arginin,  396 
relation  to  purins,  449 
Uremia,  causation  of,  465 
Uric  acid,  blood  content  in  disease,  455 
in  gout,  455 
conversion  into  urea,  400,  411 
derivation   from   inosinic   acid, 
443 
from  lactic  acid,  445 
from  tartronic  acid,  445 
diathesis,  455 
elimination  of,  452 
end  product  of  protein   catab- 
olism in  birds,  445 
extranuclear  origin  of,  444 
lactam,  450 
lactim,  450 
origin  from  xanthin,  64,  440 


Uric  acid,  oxidation  of,  447 

relation  to  allantoin,  448 
to  oxalic  acid,  449 
of  solubility  to  reaction  of 
blood,  452 
ratio  to  purin  bases,  449 
solubility  of,  451 

in  blood  plasma,  451,  452 
state  of  circulation,  450 
synthesis  from  glycocoll,  444 
threshold  value  in  gout,  456 
Uricolysis,  442,  448 

in  gout,  456 
Urinary  sulphate,  414 
Urine,  amino-acids  in,  396 
ammonia  content  of,  405 
aromatic  bodies,  relation  to  intestinal 

putrefaction,  221 
cytosin  in,  459 

elimination  of  end  products  of  pro- 
tein catabolism,  417 
glycocoll  in,  396 
metabolic  end  products  in,  465 
phosphorus  in,  460 
purin  bases  in,  445 
uracil  in,  459 
Urobilin,  fate  of,  177 

formation  in  aseptic  autolysis  of  liver, 

177 
in  urine,  417 
relation  to  bilirubin,  176 
Urobilinogen,  formation  in  intestine,  176 
Urochrome  in  urine,  417 
Uroerythrin  in  urine,  417 
Uroferric  acid  in  urine,  417 
Uterus,  autolysis  in  involution  of,  389 


Valin,  35 

Vasoconstriction  in  fever,  532 

Vegetable  diet,  mass  of,  185 
protein  in  diet,  500 
purin  content  of,  446 

Vitiatin,  composition  of,  424 


W 


Water,  formation  of,  58 

of   gastric   secretion,    variations    in 
disease,  148 
Wasting  in  fasting,  489 
Work  at  high  altitude,  541 
combustion  in,  540 

for  support  of,  538 
equivalents  of,  539 
mechanical  efficiency,  539 
mental,  thermic  equivalent,  539 
relation  to  basal   heat  production, 
538 
to    combustion    of    glucose    in 
diabetes,  302 


560 


INDEX 


Work,  relation  to  creatinin  metabolism, 
540 
to  heat  of  chemical  regulation, 
538 
of  specific  dynamic  action, 
538 
to  metabolism,  538 
to  nucleic  metabolism,  540 
to  protein  metabolism,  540 
units  of,  539 


Xanthin,  conversion  from  uric  acid,  440 
derivation  from  guanin,  440 


Xanthin,  derivation  from  hypoxanthin, 
439 
origin  from  hypoxanthin,  64 
oxidation  to  uric  acid,  64 
1-Xylose,  origin  from  d-glucuronic  acid, 

232 
Xylose  in  nucleic  acid,  430 


Yeast,  autolysis  of,  385 

Z 

Zein,  utilization  of,  379 


QP141     Tayl 
T23  Di 

1912 

c.3 


or,   A«E. 
sestion  and 


D1112 

netabolism~. 


UNIVF' 


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ill!? 


